Optically active amine derivatives and preparation process therefor

ABSTRACT

A readily available and inexpensive natural α-amino acid is converted into a compound represented by formula (1), which is then reacted with an organometallic reagent represented by formula (2) to give an optically active 5-hydroxyoxazolidine represented by formula (3), which is then treated with an acid to provide an optically active aminoketone represented by formula (4). The product is then converted into an optically active aminoalcohol represented by formula (5) or (6) by, for example reduction.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for preparing an optically active aminoalcohol derivative useful as a production intermediate for medicines, agricultural agents and so forth; for example, a process for preparing erythro-(1R,2S)-p-hydroxynorephedrine. This invention also relates to an optically active 5-hydroxyoxazolidine derivative as an important intermediate for production of the above optically active aminoalcohol derivative or a number of other optically active amine derivatives as well as a preparing process therefor. For example, an optically active 5-hydroxyoxazolidine derivative according to this invention is also very useful as a production intermediate for an azole antibacterial agent. A compound defined by general formula (1), (3) or (4) which has an asymmetric carbon having R¹ and an amino substituent represents a R— or S-form, but not a racemic mixture of the R and S forms. A compound defined by general formula (5) or (6) having two adjacent asymmetric carbons which have an amino and hydroxy substituents represents a R—S or S—R form, but not an R—R or S—S form.

2. Description of the Prior Art

Recently, optically active compounds have been increasingly needed in many applications including medicines and agricultural agents. For industrial applications, there has been strongly needed for a convenient and inexpensive process for preparing an optically active material.

The following three processes are those according to the prior art for preparing an optically active aminoalcohol derivative relating to this invention:

[1] A method, in which, after a racemic compound of the desired compound is chemically synthesized, it is then optically resolved via, for example, a diastereomer salt to give the desired optically active compound. [2] A method, in which a technique for chemical or biological asymmetric synthesis is employed to give an optically active compound from an optically inactive material.

[3] A method by a so-called “chiral pool method”, in which it starts from an optically active material and the optical active compound is obtained under prevention of racemization.

Regarding the process in [1] as “A method, in which, after a racemic compound of the desired compound is chemically synthesized, it is then optically resolved via, for example, a diastereomer salt to give the desired optically active compound”, an example may be a process according to the prior art for preparing erythro-(1R,2S)-p-hydroxynorephedrine within a category of desired optically active aminoalcohol derivatives in this invention, in which after a racemate having the desired structure is first chemically synthesized, its optical resolution is carried out using an optically active carboxylic acid such as D-tartaric acid (J. Med. Chem., 1977, 20, 7, 978).

However, as long as using a preparation process on the basis of optical resolution, it is theoretically impossible to increase the yield over 50%, unless an enantiomer is recovered and subject to a special treatment such as racemization. Furthermore, an optically active carboxylic acid and the other compounds required in resolution are generally expensive, and it is often necessary to repeat several times a process such as recrystallization. In other words, the optical resolution process requires an expensive resolving agent(s) and a multiple-stage operation, and is, therefore, industrially a high-cost preparation process.

The process in [2] as “A method, in which a technique for chemical or biological asymmetric synthesis is employed to give an optically active compound from an optically inactive material” has been significantly advanced. As examples, there are mentioned an asymmetric synthesis technique based on a chemical synthesis including the uses of asymmetric reduction catalysts or the other agents (J. Am. Chem. Soc., 1980, 102, 7932) and an asymmetric synthesis technique based on a biotechnological synthesis using an enzyme or the other agents (Japanese Patent Laid-open No. 62-29998). Unfortunately, specificity for each substrate is significantly involved in practical production and thus the process cannot be applied to all kinds of production. Furthermore, the process cannot be always inexpensive when requiring an expensive asymmetric catalyst. In practice, for an optically active aminoalcohol derivative as a desired compound in this invention, there has been available no industrially reasonable preparation processes on the basis of chemical or biotechnological technique as described above.

For the process in [3] as “A method by a so-called “chiral pool method”, in which it starts from an optically active material and the optical active compound is obtained under prevention of racemization”, there have been many problems to be solved; for example, control of racemization is difficult till now and furthermore, practical production requires multiple steps. Regarding the aminoalcohol derivatives as the desired compounds in the present invention, no processes have been reported till now, which is fully satisfactory in the industrial viewpoint.

Regarding the prior art techniques for production of the optically active aminoalcohol derivatives, only the processes, which are difficult in the industrial viewpoint and require considerably high cost. Therefore, a novel, inexpensive and more convenient processes for the production are strongly desired.

Furthermore, only the following processes [4] to [6] are known in the prior art for preparation of an optically active 5-hydroxyoxazolidine derivative as an important production intermediate in the process of this invention:

[4] A method, in which (4S)-N-(ethoxycarbonyl)-4-(2-phenylethyl)-5-oxazolidinone is reacted with 4-chloro-3-methoxyphenyl magnesium bromide (WO 95/09155).

[5] A method, in which a 5-oxazolidinone derivative is reacted with a halomethyl lithium (WO 00/53571).

[6] A method, in which a 5-oxazolidinone derivative is reacted with (trifluoromethyl)trimethylsilane (J. Org. Chem. 1998, 63 (15), 5179).

In the above [4], the compound as a starting material is a special synthetic, non-naturally, compound relating to amino-acids, which has a phenylethyl group in its side chain. The compound is, therefore, prepared by a multistep reaction and it is difficult to obtain the compound in general. In addition, it is not an inexpensive material in the viewpoint of its production cost and the process maintains a significant problem in raw material supply. Furthermore, in the above process [4], the process is extremely limited, as a single production example, to that of the compound having a 4-chloro-3-methoxyphenyl group at 5-position in the oxazolidinone ring as a principal structure, and the product is used only as a starting material for a limited application to produce a medicine (Sch39166). It cannot be said that the preparation process as an example described in [4] is a universal process, and that, regarding an optically active 5-hydroxyoxazolidine derivative, which is widely useful, its preparation process has been fully established.

Regarding the compounds described in above [5] or [6], a special functional group such as a haloalkyl group (for example, a chloromethyl group) and a trifluoromethyl group is reacted at the 5-position of the oxazolidine as a main structure, but neither aryl nor hetero ring, which are widely useful for an intermediate of a medicine and agricultural agent are not included.

Although an optically active aminoalcohol derivative having an aryl group or heterocycle has been increasingly demanded in many applications such as in the pharmaceutical and agricultural fields, no general production methods has been found in the prior art, regarding the optically active 5-hydroxyoxazolidine derivative having an aryl group or heterocycle at the 5-position as its important production intermediate.

As a known prior art for preparation of an optically active aminoketone relating to this invention, a process is known, which uses a reaction where a carboxyl group in an N-protected amino acid is converted into an acid chloride, which then undergoes Friedel-Crafts reaction (J. Am. Chem. Soc. 1981, 103, 6157). Acylation using Friedel-Crafts reaction is, however, not considered to be a general preparation method for the reasons that the reaction causes racemization, that the reaction is considerably restricted by a structure to be acylated and that sometimes an aminoketone produced cannot be isolated. Thus, an industrially practical process is needed.

SUMMARY OF THE INVENTION

An objective of this invention is to provide a stereoselective process for preparing an optically active aminoalcohol derivative represented by the general formula (5), which is useful as a production intermediate for a medicine or agricultural agent using a “readily available and inexpensive natural α-amino acid” as a starting material without racemization. Another objective is to provide technique to prepare the compound stably in a large scale with an adequate optical purity and a lower cost in an industrial viewpoint. Another objective is to provide a novel optically active 5-hydroxyoxazolidine derivative represented by general formula (3) and a novel aminoketone derivative represented by general formula (4) as important intermediates for production of the above optically active aminoalcohol derivative or many optically active amine derivatives other than the above compound as well as a novel preparation process therefor.

After intensive investigation to achieve the above objects, the present inventors have found a process for preparing an optically active aminoalcohol derivative represented by general formula (5), as a very important production intermediate for a medicine or agricultural agent, from an inexpensive and easily available starting material. Specifically, the present inventors have newly found a process for preparing the compound stereoselectively by a short process while preventing racemization, using a “natural α-L-amino acid which is industrially available with a lower cost in a large amount” and a “natural α-D-amino acid which is industrially available with a lower cost in a large amount by racemization and optical resolution of a natural α-L-amino acid or selective assimilation (Japanese Patent Laid-open No. 63-198997) as starting materials.

In other words, the present inventors have found an industrially very useful novel preparation process for an optically active aminoalcohol derivative, which is produced stably even in a large scale production, as well as with a higher optical purity and at a lower cost.

Furthermore, the present inventors have found a novel optically active 5-hydroxyoxazolidine derivative represented by general formula (3) having an aryl group or heterocycle at the 5-position in an oxazolidine ring, which is an important intermediate for preparing the above optically active aminoalcohol derivative and a novel preparation process therefore; and a novel aminoketone derivative represented by general formula (4) and a novel preparation process therefore.

Thus, the present invention has been completed.

This invention includes the following embodiments:

(I) A process for preparing an optically active aminoalcohol derivative, wherein an optically active 5-oxazolidinone derivative represented by a general formula (1):

wherein R¹ represents an unprotected or optionally protected side chain in a natural α-amino acid; and R² represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; is reacted with an organometallic reagent represented by general formula (2): R³—M  (2)

wherein R³ represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen;

to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹, R² and R³ have the same meaning as defined above; which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4):

wherein R¹ and R³ have the same meanings as defined above; and R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group;

which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to stereoselectively provide an optically active aminoalcohol derivative represented by general formula (5):

wherein R¹, R³ and R⁴ have the same meanings as defined above; provided that configuration of R¹ attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone derivative represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (5) is an erythro configuration.

(II) A process for preparing an aminoalcohol derivative, wherein an optically active 5-oxazolidinone derivative represented by a general formula (1):

wherein R¹ represents an unprotected or optionally protected side chain in a natural α-amino acid; and R² represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; is reacted with an organometallic reagent represented by general formula (2): R³—M  (2)

wherein R³ represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen,

to form an optically active 5-hydroxyoxazolidine represented derivative by general formula (3):

wherein R¹, R² and R³ have the same meanings as defined above;

which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4):

wherein R¹ and R³ have the same meanings as defined above; and R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group;

which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to provide an optically active aminoalcohol derivative represented by general formula (5):

wherein R¹, R³ and R⁴ have the same meanings as defined above,

and then, when R⁴ is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6):

wherein R¹ and R³ have the same meanings as defined above;

provided that configuration of R¹ attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone derivative represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (6) is an erythro configuration.

(III) The process for preparing an optically active aminoalcohol derivative as described in (I) or (II), wherein R¹ represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl; R² represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.

(IV) The process for preparing an optically active aminoalcohol as described in (I) or (II), wherein R³ is represented by general formula (7):

wherein Y represents halogen; or by general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.

(V) The process for preparing an optically active aminoalcohol as described in (I) or (II) wherein R¹ represents methyl; and R³ is represented by general formula (8).

(VI) An optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R² represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and R³ represents optionally substituted aryl or optionally substituted heterocycle.

(VII) The optically active 5-hydroxyoxazolidine derivative as described in (VI), wherein R¹ represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl.

(VIII) The optically active 5-hydroxyoxazolidine derivative as described in (VI) or (VII) wherein R² represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.

(IX) The optically active 5-hydroxyoxazolidine as described in (VIII) wherein R³ is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.

(X) The optically active 5-hydroxyoxazolidine as described in (IX) wherein R¹ is methyl.

(XI) A process for preparing an optically active 5-hydroxyoxazolidine wherein an optically active 5-oxazolidinone derivative represented by general formula (1):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R² represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl;

is reacted with an organometallic reagent represented by general formula (2): R³—M  (2)

wherein R³ represents optionally substituted aryl or optionally substituted heterocycle; M is one selected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen; to provide an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹, R² and R³ have the same meanings as defined above.

(XII) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XI) wherein R¹ represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl.

(XIII) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XI) or (XII) wherein R² represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.

(XIV) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XIII) wherein R³ is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.

(XV) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XIV) wherein R¹ is methyl.

(XVI) The process for preparing an optically active 5-hydroxyoxazolidine derivative as described in (XI) or (XII) wherein M in general formula (2) is MgX wherein X is as defined above.

(XVII) An aminoketone represented by general formula (4a):

wherein R^(1a) represents methyl: R^(4a) represents hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl; R^(3a) represents 4-benzyloxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl or 3-indolyl.

(XVIII) A process for preparing an aminoketone derivative wherein a 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R² represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and R³ represents optionally substituted aryl or optionally substituted heterocycle;

is treated under acidic conditions to form an aminoketone derivative represented by general formula (4):

wherein R¹ and R³ are as defined above; R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group.

(XIX) An optically active alcohol derivative represented by general formula (5a):

wherein R^(1a) represents methyl; R^(3b) represents 4-benzyloxyphenyl; R^(4b) represents benzyloxycarbonyl; and configuration between the amino group and the hydroxy group is erythro.

(XX) A process for preparing an optically active aminoalcohol derivative wherein an optically active aminoketone represented by general formula (4b):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R^(3c) is represented by general formula (8):

R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl; is treated with a reducing agent or catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol derivative represented by general formula (5b):

wherein R¹, R^(3c) and R⁴ are as defined above; provided that configuration of R¹ attached to the asymmetric carbon at the 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (5b) is erythro.

(XXI) A process for preparing an optically active aminoalcohol wherein an optically active aminoketone derivative represented by general formula (4b):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R^(3c) is represented by general formula (8):

R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl; is treated with a reducing agent or catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol derivative represented by general formula (5b):

wherein R¹, R^(3c) and R⁴ are as defined above, and when R⁴ is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6a):

wherein R¹ and R^(3c) are as defined above; provided that configuration of R¹ attached to the asymmetric carbon at the 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (6a) is erythro.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

This invention will be detailed.

The term “unprotected side chain or optionally protected side chain in a natural α-amino acid” as used herein refers to a side chain on an α-carbon such as alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine and ornithine for, for example, an “unprotected side chain in a natural α-amino acid”.

An “optionally protected side chain” may be a side chain on an α-carbon in any of the above natural α-amino acid in which a given functional group is protected by a protective group. The protective group may be any of those commonly used in a process known by those skilled in the art. For example, it may be a protective group for an amino, thiol, hydroxy, phenol or carboxyl group used in common preparation of an amino acid.

An “optionally substituted alkyl” means a substituted alkyl at an optional position(s). Examples of the alkyl group include methyl, ethyl, isopropyl, tert-butyl, pentyl, hexyl, octyl, decyl and allyl. Examples of the substituents used include hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

An “optionally substituted aryl” means a substituted aryl at an optional position(s). Examples of the aryl group include phenyl, naphthyl, anthracenyl, fluorenyl and phenanthrenyl. Examples of a substituent(s) used include alkyls such as methyl, tert-butyl and benzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

An “optionally substituted aralkyl” means a substituted aralkyl at an optional position(s). Examples of the aralkyl group include benzyl, naphthylmethyl, phenylethyl and 9-fluorenylmethyl. Examples of a substituent(s) used include alkyls such as methyl, tert-butyl and benzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

An “optionally substituted heterocycle” means an substituted heterocycle at an optional position(s).

Examples of the heterocycle include tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, furyl, thienyl, pyridyl, furfuryl, thenyl, pyridylmethyl, pyrimidyl, pyrazyl, imidazoyl, imidazoylmethyl, indolyl, indolylmethyl, isoquinolyl, quinolyl and thiazolyl. Examples of a substituent used include alkyls such as methyl, tert-butyl and benzyl; cycloalkyls such as cyclopropyl, cyclopentyl and cyclohexyl; phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

A “heterocyclealkyl” in an optionally substituted heterocyclealkyl means an alkyl substituted with one or more heterocycles at one or more positions, and the “heterocyclealkyl” itself is optionally substituted. Examples of the heterocycle, the alkyl and the substituent therefor may be those described above for an “optionally substituted alkyl” and an “optionally substituted heterocycle”.

An “optionally substituted alkyloxycarbonyl” means an optionally substituted alkyloxycarbonyl at given one or more positions. Examples of the alkyloxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, decyloxycarbonyl and allyloxycarbonyl. Examples of the substituent(s) used include hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

An “optionally substituted aryloxycarbonyl” means an optionally substituted aryloxycarbonyl at given one or more positions. Examples of the aryloxycarbonyl include phenoxycarbonyl, naphthyloxycarbonyl, anthracenyloxycarbonyl, fluorenyloxycarbonyl and phenanthrenyloxycarbonyl. Examples of the substituent(s) used include alkyls and aralkyls such as methyl, tert-butyl and benzyl; cycloalkyls derived from cyclopropane, cyclopentane and cyclohexane (for example, cyclopropyl, cyclopentyl and cyclohexyl); phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

An “optionally substituted aralkyloxycarbonyl” means an optionally substituted aralkyloxycarbonyl at given one or more positions. Examples of the aralkyloxycarbonyl include benzyloxycarbonyl, naphthylmethyloxycarbonyl, phenylethyloxycarbonyl and 9-fluorenylmethyloxycarbonyl. Examples of the substituent(s) used include alkyls and aralkyls; such as methyl, tert-butyl and benzyl; cycloalkyls derived from cyclopropane, cyclopentane and cyclohexane (for example, cyclopropyl, cyclopentyl and cyclohexyl); phenyl; hydroxy; alkoxys such as methoxy, benzyloxy and methoxyethoxy; phenoxy; nitro; amino; amide; carboxyl; alkoxycarbonyl; phenoxycarbonyl; and halogens such as fluorine, chlorine, bromine and iodine.

Each of the above optionally substituted groups may have one or more substituents. When it has a plurality of substituents, each substituent may be independently selected from those described above.

A “halogen” may be fluorine, chlorine, bromine or iodine. Two “Ys” in general formula (7) may be the same or different.

A “reducing agent” means a reagent which can reduce a ketone moiety in the aminoketone derivative represented by general formula (4) into an alcohol moiety, including borane reagents such as borane-tetrahydrofuran complex; borohydride reagents such as sodium borohydride, zinc borohydride and sodium trimethoxy borohydride; alkylaluminum reagents such as diisopropylaluminum hydride; aluminum hydride reagents such as lithium aluminum hydride and lithium trialkoxyaluminum hydride; silane reagents such as trichlorosilane and triethylsilane; sodium metal in liquid ammonia; and magnesium metal in an alcohol.

“Catalytic hydrogenation with a metal catalyst” means reduction of a ketone moiety in the aminoketone derivative represented by general formula (4) into an alcohol moiety by catalytic hydrogenation in the presence of a metal catalyst. Examples of the metal catalyst include nickel catalysts such as Raney nickel, platinum catalysts such as platinum oxide, palladium catalysts such as palladium-carbon or rhodium catalysts such as chlorotris(triphenylphosphine)rhodium which is also known as a Wilkinson catalyst.

“Erythro configuration” is a term indicating a relative configuration of two adjacent asymmetric carbons. For a compound represented by general formula (5) or (6), when the amino and the hydroxy groups as substituents are in the same side in a Ficher projection formula, they have erythro configuration.

Tables 1 to 21 show representative optically active 5-hydroxyoxazolidine derivatives within general formula (3); Tables 22 to 27 show representative optically active aminoketone derivatives within general formula (4); and Tables 28 to 39 show representative optically active aminoalcohol derivatives within general formula (5) or (6), but this invention is not limited to these exemplified compounds. In these Tables, Ph is phenyl or phenylene; Me is methyl; Boc is tert-butoxycarbonyl as a protective group.

TABLE 1

Example Compound No. R2— R3— 1001 PhCH₂— p-PhCH₂OPh— 1002 CH₃— p-PhCH₂OPh— 1003 9-Fluorenylmethyl- p-PhCH₂OPh— 1004 (CH₃)₃C— o-PhCH₂OPh— 1005 CH₃— m-PhCH₂OPh— 1006 PhCH₂— p-NO₂Ph— 1007 (CH₃)₃C— p-MeOPh— 1008 PhCH₂— p-HOPh— 1009 (CH₃)₃C— Ph— 1010 PhCH₂— p-FPh 1011 PhCH₂— 3-Indolyl- 1012 CH₃— 3-Indolyl- 1013 PhCH₂—

1014 PhCH₂—

1015 (CH₃)₃C— p-PhCH₂OPh— 1016 CH₃CH₂— p-PhCH₂OPh— 1017 PhCH₂— o-PhCH₂OPh— 1018 (CH₃)₃C— m-PhCH₂OPh— 1019 CH₃CH₂— o-PhCH₂OPh— 1020 PhCH₂— p-MeOPh— 1021 (CH₃)₃C— m-MeOPh— 1022 PhCH₂— Ph 1023 PhCH₂— p-CH₃Ph— 1024 (CH₃)₃C— p-ClPh— 1025 (CH₃)₃C— 3-Indolyl- 1026 9-Fluorenylmethyl- 3-Indolyl- 1027 (CH₃)₃C—

1028 9-Fluorenylmethyl-

1029 (CH₃)₃C—

1030 PhCH₂—

1031 (CH3)₂CH—

TABLE 2

Example Compound No. R2— R3— 2001 PhCH₂— p-PhCH₂OPh— 2002 CH₃— p-PhCH₂OPh— 2003 9-Fluorenylmethyl- p-PhCH₂OPh— 2004 (CH₃)₃C— o-PhCH₂OPh— 2005 CH₃— m-PhCH₂OPh— 2006 PhCH₂— p-NO₂Ph— 2007 (CH₃)₃C— p-MeOPh— 2008 PhCH₂— p-HOPh— 2009 (CH₃)₃C— Ph— 2010 PhCH₂— p-FPh 2011 PhCH₂— 3-Indolyl- 2012 CH₃— 3-Indolyl- 2013 PhCH₂—

2014 PhCH₂—

2015 (CH₃)₃C— p-PhCH₂OPh— 2016 CH₃CH₂— p-PhCH₂OPh— 2017 PhCH₂— o-PhCH₂OPh— 2018 (CH₃)₃C— m-PhCH₂OPh— 2019 CH₃CH₂— o-PhCH₂OPh— 2020 PhCH₂— p-MeOPh— 2021 (CH₃)₃C— m-MeOPh— 2022 PhCH₂— Ph 2023 PhCH₂— p-CH₃Ph— 2024 (CH₃)₃C— p-ClPh— 2025 (CH₃)₃C— 3-Indolyl- 2026 9-Fluorenylmethyl- 3-Indolyl- 2027 (CH₃)₃C—

2028 9-Fluorenylmethyl-

2029 (CH₃)₃C—

2030 PhCH₂—

2031 (CH3)₂CH—

TABLE 3

Example Compound No. R2— R3— 3001 PhCH₂— p-PhCH₂OPh— 3002 CH₃— p-PhCH₂OPh— 3003 9-Fluorenylmethyl- p-PhCH₂OPh— 3004 (CH₃)₃C— o-PhCH₂OPh— 3005 CH₃— m-PhCH₂OPh— 3006 PhCH₂— p-NO₂Ph— 3007 (CH₃)₃C— p-MeOPh— 3008 PhCH₂— p-HOPh— 3009 (CH₃)₃C— Ph— 3010 PhCH₂— p-FPh 3011 PhCH₂— 3-Indolyl- 3012 CH₃— 3-Indolyl- 3013 PhCH₂—

3014 PhCH₂—

3015 (CH₃)₃C— p-PhCH₂OPh— 3016 CH₃CH₂— p-PhCH₂OPh— 3017 PhCH₂— o-PhCH₂OPh— 3018 (CH₃)₃C— m-PhCH₂OPh— 3019 CH₃CH₂— o-PhCH₂OPh— 3020 PhCH₂— p-MeOPh— 3021 (CH₃)₃C— m-MeOPh— 3022 PhCH₂— Ph 3023 PhCH₂— p-CH₃Ph— 3024 (CH₃)₃C— p-ClPh— 3025 (CH₃)₃C— 3-Indolyl- 3026 9-Fluorenylmethyl- 3-Indolyl- 3027 (CH₃)₃C—

3028 9-Fluorenylmethyl-

3029 (CH₃)₃C—

3030 PhCH₂—

3031 (CH3)₂CH—

TABLE 4

Example Compound No. R2— R3— 4001 PhCH₂— p-PhCH₂OPh— 4002 CH₃— p-PhCH₂OPh— 4003 9-Fluorenylmethyl- p-PhCH₂OPh— 4004 (CH₃)₃C— o-PhCH₂OPh— 4005 CH₃— m-PhCH₂OPh— 4006 PhCH₂— p-NO₂Ph— 4007 (CH₃)₃C— p-MeOPh— 4008 PhCH₂— p-HOPh— 4009 (CH₃)₃C— Ph— 4010 PhCH₂— p-FPh 4011 PhCH₂— 3-Indolyl- 4012 CH₃— 3-Indolyl- 4013 PhCH₂—

4014 PhCH₂—

4015 (CH₃)₃C— p-PhCH₂OPh— 4016 CH₃CH₂— p-PhCH₂OPh— 4017 PhCH₂— o-PhCH₂OPh— 4018 (CH₃)₃C— m-PhCH₂OPh— 4019 CH₃CH₂— o-PhCH₂OPh— 4020 PhCH₂— p-MeOPh— 4021 (CH₃)₃C— m-MeOPh— 4022 PhCH₂— Ph 4023 PhCH₂— p-CH₃Ph— 4024 (CH₃)₃C— p-ClPh— 4025 (CH₃)₃C— 3-Indolyl- 4026 9-Fluorenylmethyl- 3-Indolyl- 4027 (CH₃)₃C—

4028 9-Fluorenylmethyl-

4029 (CH₃)₃C—

4030 PhCH₂—

4031 (CH3)₂CH—

TABLE 5

Example Compound No. R2— R3— 5001 PhCH₂— p-PhCH₂OPh— 5002 CH₃— p-PhCH₂OPh— 5003 9-Fluorenylmethyl- p-PhCH₂OPh— 5004 (CH₃)₃C— o-PhCH₂OPh— 5005 CH₃— m-PhCH₂OPh— 5006 PhCH₂— p-NO₂Ph— 5007 (CH₃)₃C— p-MeOPh— 5008 PhCH₂— p-HOPh— 5009 (CH₃)₃C— Ph— 5010 PhCH₂— p-FPh 5011 PhCH₂— 3-Indolyl- 5012 CH₃— 3-Indolyl- 5013 PhCH₂—

5014 PhCH₂—

5015 (CH₃)₃C— p-PhCH₂OPh— 5016 CH₃CH₂— p-PhCH₂OPh— 5017 PhCH₂— o-PhCH₂OPh— 5018 (CH₃)₃C— m-PhCH₂OPh— 5019 CH₃CH₂— o-PhCH₂OPh— 5020 PhCH₂— p-MeOPh— 5021 (CH₃)₃C— m-MeOPh— 5022 PhCH₂— Ph 5023 PhCH₂— p-CH₃Ph— 5024 (CH₃)₃C— p-ClPh— 5025 (CH₃)₃C— 3-Indolyl- 5026 9-Fluorenylmethyl- 3-Indolyl- 5027 (CH₃)₃C—

5028 9-Fluorenylmethyl-

5029 (CH₃)₃C—

5030 PhCH₂—

5031 (CH3)₂CH—

TABLE 6

Example Compound No. R2— R3— 6001 PhCH₂— p-PhCH₂OPh— 6002 CH₃— p-PhCH₂OPh— 6003 9-Fluorenylmethyl- p-PhCH₂OPh— 6004 (CH₃)₃C— o-PhCH₂OPh— 6005 CH₃— m-PhCH₂OPh— 6006 PhCH₂— p-NO₂Ph— 6007 (CH₃)₃C— p-MeOPh— 6008 PhCH₂— p-HOPh— 6009 (CH₃)₃C— Ph— 6010 PhCH₂— p-FPh 6011 PhCH₂— 3-Indolyl- 6012 CH₃— 3-Indolyl- 6013 PhCH₂—

6014 PhCH₂—

6015 (CH₃)₃C— p-PhCH₂OPh— 6016 CH₃CH₂— p-PhCH₂OPh— 6017 PhCH₂— o-PhCH₂OPh— 6018 (CH₃)₃C— m-PhCH₂OPh— 6019 CH₃CH₂— o-PhCH₂OPh— 6020 PhCH₂— p-MeOPh— 6021 (CH₃)₃C— m-MeOPh— 6022 PhCH₂— Ph 6023 PhCH₂— p-CH₃Ph— 6024 (CH₃)₃C— p-ClPh— 6025 (CH₃)₃C— 3-Indolyl- 6026 9-Fluorenylmethyl- 3-Indolyl- 6027 (CH₃)₃C—

6028 9-Fluorenylmethyl-

6029 (CH₃)₃C—

6030 PhCH₂—

6031 (CH3)₂CH—

TABLE 7

Example Compound No. R2— R3— 7001 PhCH₂— p-PhCH₂OPh— 7002 CH₃— p-PhCH₂OPh— 7003 9-Fluorenylmethyl- p-PhCH₂OPh— 7004 (CH₃)₃C— o-PhCH₂OPh— 7005 CH₃— m-PhCH₂OPh— 7006 PhCH₂— p-NO₂Ph— 7007 (CH₃)₃C— p-MeOPh— 7008 PhCH₂— p-HOPh— 7009 (CH₃)₃C— Ph— 7010 PhCH₂— p-FPh 7011 PhCH₂— 3-Indolyl- 7012 CH₃— 3-Indolyl- 7013 PhCH₂—

7014 PhCH₂—

7015 (CH₃)₃C— p-PhCH₂OPh— 7016 CH₃CH₂— p-PhCH₂OPh— 7017 PhCH₂— o-PhCH₂OPh— 7018 (CH₃)₃C— m-PhCH₂OPh— 7019 CH₃CH₂— o-PhCH₂OPh— 7020 PhCH₂— p-MeOPh— 7021 (CH₃)₃C— m-MeOPh— 7022 PhCH₂— Ph 7023 PhCH₂— p-CH₃Ph— 7024 (CH₃)₃C— p-ClPh— 7025 (CH₃)₃C— 3-Indolyl- 7026 9-Fluorenylmethyl- 3-Indolyl- 7027 (CH₃)₃C—

7028 9-Fluorenylmethyl-

7029 (CH₃)₃C—

7030 PhCH₂—

7031 (CH3)₂CH—

TABLE 8

Example Compound No. R2— R3— 8001 PhCH₂— p-PhCH₂OPh— 8002 CH₃— p-PhCH₂OPh— 8003 9-Fluorenylmethyl- p-PhCH₂OPh— 8004 (CH₃)₃C— o-PhCH₂OPh— 8005 CH₃— m-PhCH₂OPh— 8006 PhCH₂— p-NO₂Ph— 8007 (CH₃)₃C— p-MeOPh— 8008 PhCH₂— p-HOPh— 8009 (CH₃)₃C— Ph— 8010 PhCH₂— p-FPh 8011 PhCH₂— 3-Indolyl- 8012 CH₃— 3-Indolyl- 8013 PhCH₂—

8014 PhCH₂—

8015 (CH₃)₃C— p-PhCH₂OPh— 8016 CH₃CH₂— p-PhCH₂OPh— 8017 PhCH₂— o-PhCH₂OPh— 8018 (CH₃)₃C— m-PhCH₂OPh— 8019 CH₃CH₂— o-PhCH₂OPh— 8020 PhCH₂— p-MeOPh— 8021 (CH₃)₃C— m-MeOPh— 8022 PhCH₂— Ph 8023 PhCH₂— p-CH₃Ph— 8024 (CH₃)₃C— p-ClPh— 8025 (CH₃)₃C— 3-Indolyl- 8026 9-Fluorenylmethyl- 3-Indolyl- 8027 (CH₃)₃C—

8028 9-Fluorenylmethyl-

8029 (CH₃)₃C—

8030 PhCH₂—

8031 (CH3)₂CH—

TABLE 9

Example Compound No. R2— R3— 9001 PhCH₂— p-PhCH₂OPh— 9002 CH₃— p-PhCH₂OPh— 9003 9-Fluorenylmethyl- p-PhCH₂OPh— 9004 (CH₃)₃C— o-PhCH₂OPh— 9005 CH₃— m-PhCH₂OPh— 9006 PhCH₂— p-NO₂Ph— 9007 (CH₃)₃C— p-MeOPh— 9008 PhCH₂— p-HOPh— 9009 (CH₃)₃C— Ph— 9010 PhCH₂— p-FPh 9011 PhCH₂— 3-Indolyl- 9012 CH₃— 3-Indolyl- 9013 PhCH₂—

9014 PhCH₂—

9015 (CH₃)₃C— p-PhCH₂OPh— 9016 CH₃CH₂— p-PhCH₂OPh— 9017 PhCH₂— o-PhCH₂OPh— 9018 (CH₃)₃C— m-PhCH₂OPh— 9019 CH₃CH₂— o-PhCH₂OPh— 9020 PhCH₂— p-MeOPh— 9021 (CH₃)₃C— m-MeOPh— 9022 PhCH₂— Ph 9023 PhCH₂— p-CH₃Ph— 9024 (CH₃)₃C— p-ClPh— 9025 (CH₃)₃C— 3-Indolyl- 9026 9-Fluorenylmethyl- 3-Indolyl- 9027 (CH₃)₃C—

9028 9-Fluorenylmethyl-

9029 (CH₃)₃C—

9030 PhCH₂—

9031 (CH3)₂CH—

TABLE 10

Example Compound No. R2— R3— 10001 PhCH₂— p-PhCH₂OPh— 10002 CH₃— p-PhCH₂OPh— 10003 9-Fluorenylmethyl- p-PhCH₂OPh— 10004 (CH₃)₃C— o-PhCH₂OPh— 10005 CH₃— m-PhCH₂OPh— 10006 PhCH₂— p-NO₂Ph— 10007 (CH₃)₃C— p-MeOPh— 10008 PhCH₂— p-HOPh— 10009 (CH₃)₃C— Ph— 10010 PhCH₂— p-FPh 10011 PhCH₂— 3-Indolyl- 10012 CH₃— 3-Indolyl- 10013 PhCH₂—

10014 PhCH₂—

10015 (CH₃)₃C— p-PhCH₂OPh— 10016 CH₃CH₂— p-PhCH₂OPh— 10017 PhCH₂— o-PhCH₂OPh— 10018 (CH₃)₃C— m-PhCH₂OPh— 10019 CH₃CH₂— o-PhCH₂OPh— 10020 PhCH₂— p-MeOPh— 10021 (CH₃)₃C— m-MeOPh— 10022 PhCH₂— Ph 10023 PhCH₂— p-CH₃Ph— 10024 (CH₃)₃C— p-ClPh— 10025 (CH₃)₃C— 3-Indolyl- 10026 9-Fluorenylmethyl- 3-Indolyl- 10027 (CH₃)₃C—

10028 9-Fluorenylmethyl-

10029 (CH₃)₃C—

10030 PhCH₂—

10031 (CH3)₂CH—

TABLE 11

Example Compound No. R2— R3— 11001 PhCH₂— p-PhCH₂OPh— 11002 CH₃— p-PhCH₂OPh— 11003 9-Fluorenylmethyl- p-PhCH₂OPh— 11004 (CH₃)₃C— o-PhCH₂OPh— 11005 CH₃— m-PhCH₂OPh— 11006 PhCH₂— p-NO₂Ph— 11007 (CH₃)₃C— p-MeOPh— 11008 PhCH₂— p-HOPh— 11009 (CH₃)₃C— Ph— 11010 PhCH₂— p-FPh 11011 PhCH₂— 3-Indolyl- 11012 CH₃— 3-Indolyl- 11013 PhCH₂—

11014 PhCH₂—

11015 (CH₃)₃C— p-PhCH₂OPh— 11016 CH₃CH₂— p-PhCH₂OPh— 11017 PhCH₂— o-PhCH₂OPh— 11018 (CH₃)₃C— m-PhCH₂OPh— 11019 CH₃CH₂— o-PhCH₂OPh— 11020 PhCH₂— p-MeOPh— 11021 (CH₃)₃C— m-MeOPh— 11022 PhCH₂— Ph 11023 PhCH₂— p-CH₃Ph— 11024 (CH₃)₃C— p-ClPh— 11025 (CH₃)₃C— 3-Indolyl- 11026 9-Fluorenylmethyl- 3-Indolyl- 11027 (CH₃)₃C—

11028 9-Fluorenylmethyl-

11029 (CH₃)₃C—

11030 PhCH₂—

11031 (CH3)₂CH—

TABLE 12

Example Compound No. R2— R3— 12001 PhCH₂— p-PhCH₂OPh— 12002 CH₃— p-PhCH₂OPh— 12003 9-Fluorenylmethyl- p-PhCH₂OPh— 12004 (CH₃)₃C— o-PhCH₂OPh— 12005 CH₃— m-PhCH₂OPh— 12006 PhCH₂— p-NO₂Ph— 12007 (CH₃)₃C— p-MeOPh— 12008 PhCH₂— p-HOPh— 12009 (CH₃)₃C— Ph— 12010 PhCH₂— p-FPh 12011 PhCH₂— 3-Indolyl- 12012 CH₃— 3-Indolyl- 12013 PhCH₂—

12014 PhCH₂—

12015 (CH₃)₃C— p-PhCH₂OPh— 12016 CH₃CH₂— p-PhCH₂OPh— 12017 PhCH₂— o-PhCH₂OPh— 12018 (CH₃)₃C— m-PhCH₂OPh— 12019 CH₃CH₂— o-PhCH₂OPh— 12020 PhCH₂— p-MeOPh— 12021 (CH₃)₃C— m-MeOPh— 12022 PhCH₂— Ph 12023 PhCH₂— p-CH₃Ph— 12024 (CH₃)₃C— p-ClPh— 12025 (CH₃)₃C— 3-Indolyl- 12026 9-Fluorenylmethyl- 3-Indolyl- 12027 (CH₃)₃C—

12028 9-Fluorenylmethyl-

12029 (CH₃)₃C—

12030 PhCH₂—

12031 (CH3)₂CH—

TABLE 13

Example Compound No. R2— R3— 13001 PhCH₂— p-PhCH₂OPh— 13002 CH₃— p-PhCH₂OPh— 13003 9-Fluorenylmethyl- p-PhCH₂OPh— 13004 (CH₃)₃C— o-PhCH₂OPh— 13005 CH₃— m-PhCH₂OPh— 13006 PhCH₂— p-NO₂Ph— 13007 (CH₃)₃C— p-MeOPh— 13008 PhCH₂— p-HOPh— 13009 (CH₃)₃C— Ph— 13010 PhCH₂— p-FPh 13011 PhCH₂— 3-Indolyl- 13012 CH₃— 3-Indolyl- 13013 PhCH₂—

13014 PhCH₂—

13015 (CH₃)₃C— p-PhCH₂OPh— 13016 CH₃CH₂— p-PhCH₂OPh— 13017 PhCH₂— o-PhCH₂OPh— 13018 (CH₃)₃C— m-PhCH₂OPh— 13019 CH₃CH₂— o-PhCH₂OPh— 13020 PhCH₂— p-MeOPh— 13021 (CH₃)₃C— m-MeOPh— 13022 PhCH₂— Ph 13023 PhCH₂— p-CH₃Ph— 13024 (CH₃)₃C— p-ClPh— 13025 (CH₃)₃C— 3-Indolyl- 13026 9-Fluorenylmethyl- 3-Indolyl- 13027 (CH₃)₃C—

13028 9-Fluorenylmethyl-

13029 (CH₃)₃C—

13030 PhCH₂—

13031 (CH3)₂CH—

TABLE 14

Example Compound No. R2— R3— 14001 PhCH₂— p-PhCH₂OPh— 14002 CH₃— p-PhCH₂OPh— 14003 9-Fluorenylmethyl- p-PhCH₂OPh— 14004 (CH₃)₃C— o-PhCH₂OPh— 14005 CH₃— m-PhCH₂OPh— 14006 PhCH₂— p-NO₂Ph— 14007 (CH₃)₃C— p-MeOPh— 14008 PhCH₂— p-HOPh— 14009 (CH₃)₃C— Ph— 14010 PhCH₂— p-FPh 14011 PhCH₂— 3-Indolyl- 14012 CH₃— 3-Indolyl- 14013 PhCH₂—

14014 PhCH₂—

14015 (CH₃)₃C— p-PhCH₂OPh— 14016 CH₃CH₂— p-PhCH₂OPh— 14017 PhCH₂— o-PhCH₂OPh— 14018 (CH₃)₃C— m-PhCH₂OPh— 14019 CH₃CH₂— o-PhCH₂OPh— 14020 PhCH₂— p-MeOPh— 14021 (CH₃)₃C— m-MeOPh— 14022 PhCH₂— Ph 14023 PhCH₂— p-CH₃Ph— 14024 (CH₃)₃C— p-ClPh— 14025 (CH₃)₃C— 3-Indolyl- 14026 9-Fluorenylmethyl- 3-Indolyl- 14027 (CH₃)₃C—

14028 9-Fluorenylmethyl-

14029 (CH₃)₃C—

14030 PhCH₂—

14031 (CH3)₂CH—

TABLE 15

Example Compound No. R2— R3— 15001 PhCH₂— p-PhCH₂OPh— 15002 CH₃— p-PhCH₂OPh— 15003 9-Fluorenylmethyl- p-PhCH₂OPh— 15004 (CH₃)₃C— o-PhCH₂OPh— 15005 CH₃— m-PhCH₂OPh— 15006 PhCH₂— p-NO₂Ph— 15007 (CH₃)₃C— p-MeOPh— 15008 PhCH₂— p-HOPh— 15009 (CH₃)₃C— Ph— 15010 PhCH₂— p-FPh 15011 PhCH₂— 3-Indolyl- 15012 CH₃— 3-Indolyl- 15013 PhCH₂—

15014 PhCH₂—

15015 (CH₃)₃C— p-PhCH₂OPh— 15016 CH₃CH₂— p-PhCH₂OPh— 15017 PhCH₂— o-PhCH₂OPh— 15018 (CH₃)₃C— m-PhCH₂OPh— 15019 CH₃CH₂— o-PhCH₂OPh— 15020 PhCH₂— p-MeOPh— 15021 (CH₃)₃C— m-MeOPh— 15022 PhCH₂— Ph 15023 PhCH₂— p-CH₃Ph— 15024 (CH₃)₃C— p-ClPh— 15025 (CH₃)₃C— 3-Indolyl- 15026 9-Fluorenylmethyl- 3-Indolyl- 15027 (CH₃)₃C—

15028 9-Fluorenylmethyl-

15029 (CH₃)₃C—

15030 PhCH₂—

15031 (CH3)₂CH—

TABLE 16

Example Compound No. R2— R3— 16001 PhCH₂— p-PhCH₂OPh— 16002 CH₃— p-PhCH₂OPh— 16003 9-Fluorenylmethyl- p-PhCH₂OPh— 16004 (CH₃)₃C— o-PhCH₂OPh— 16005 CH₃— m-PhCH₂OPh— 16006 PhCH₂— p-NO₂Ph— 16007 (CH₃)₃C— p-MeOPh— 16008 PhCH₂— p-HOPh— 16009 (CH₃)₃C— Ph— 16010 PhCH₂— p-FPh 16011 PhCH₂— 3-Indolyl- 16012 CH₃— 3-Indolyl- 16013 PhCH₂—

16014 PhCH₂—

16015 (CH₃)₃C— p-PhCH₂OPh— 16016 CH₃CH₂— p-PhCH₂OPh— 16017 PhCH₂— o-PhCH₂OPh— 16018 (CH₃)₃C— m-PhCH₂OPh— 16019 CH₃CH₂— o-PhCH₂OPh— 16020 PhCH₂— p-MeOPh— 16021 (CH₃)₃C— m-MeOPh— 16022 PhCH₂— Ph 16023 PhCH₂— p-CH₃Ph— 16024 (CH₃)₃C— p-ClPh— 16025 (CH₃)₃C— 3-Indolyl- 16026 9-Fluorenylmethyl- 3-Indolyl- 16027 (CH₃)₃C—

16028 9-Fluorenylmethyl-

16029 (CH₃)₃C—

16030 PhCH₂—

16031 (CH3)₂CH—

TABLE 17

Example Compound No. R2— R3— 17001 PhCH₂— p-PhCH₂OPh— 17002 CH₃— p-PhCH₂OPh— 17003 9-Fluorenylmethyl- p-PhCH₂OPh— 17004 (CH₃)₃C— o-PhCH₂OPh— 17005 CH₃— m-PhCH₂OPh— 17006 PhCH₂— p-NO₂Ph— 17007 (CH₃)₃C— p-MeOPh— 17008 PhCH₂— p-HOPh— 17009 (CH₃)₃C— Ph— 17010 PhCH₂— p-FPh 17011 PhCH₂— 3-Indolyl- 17012 CH₃— 3-Indolyl- 17013 PhCH₂—

17014 PhCH₂—

17015 (CH₃)₃C— p-PhCH₂OPh— 17016 CH₃CH₂— p-PhCH₂OPh— 17017 PhCH₂— o-PhCH₂OPh— 17018 (CH₃)₃C— m-PhCH₂OPh— 17019 CH₃CH₂— o-PhCH₂OPh— 17020 PhCH₂— p-MeOPh— 17021 (CH₃)₃C— m-MeOPh— 17022 PhCH₂— Ph 17023 PhCH₂— p-CH₃Ph— 17024 (CH₃)₃C— p-ClPh— 17025 (CH₃)₃C— 3-Indolyl- 17026 9-Fluorenylmethyl- 3-Indolyl- 17027 (CH₃)₃C—

17028 9-Fluorenylmethyl-

17029 (CH₃)₃C—

17030 PhCH₂—

17031 (CH3)₂CH—

TABLE 18

Example Compound No. R2— R3— 18001 PhCH₂— p-PhCH₂OPh— 18002 CH₃— p-PhCH₂OPh— 18003 9-Fluorenylmethyl- p-PhCH₂OPh— 18004 (CH₃)₃C— o-PhCH₂OPh— 18005 CH₃— m-PhCH₂OPh— 18006 PhCH₂— p-NO₂Ph— 18007 (CH₃)₃C— p-MeOPh— 18008 PhCH₂— p-HOPh— 18009 (CH₃)₃C— Ph— 18010 PhCH₂— p-FPh 18011 PhCH₂— 3-Indolyl- 18012 CH₃— 3-Indolyl- 18013 PhCH₂—

18014 PhCH₂—

18015 (CH₃)₃C— p-PhCH₂OPh— 18016 CH₃CH₂— p-PhCH₂OPh— 18017 PhCH₂— o-PhCH₂OPh— 18018 (CH₃)₃C— m-PhCH₂OPh— 18019 CH₃CH₂— o-PhCH₂OPh— 18020 PhCH₂— p-MeOPh— 18021 (CH₃)₃C— m-MeOPh— 18022 PhCH₂— Ph 18023 PhCH₂— p-CH₃Ph— 18024 (CH₃)₃C— p-ClPh— 18025 (CH₃)₃C— 3-Indolyl- 18026 9-Fluorenylmethyl- 3-Indolyl- 18027 (CH₃)₃C—

18028 9-Fluorenylmethyl-

18029 (CH₃)₃C—

18030 PhCH₂—

18031 (CH3)₂CH—

TABLE 19

Example Compound No. R2— R3— 19001 PhCH₂— p-PhCH₂OPh— 19002 CH₃— p-PhCH₂OPh— 19003 9-Fluorenylmethyl- p-PhCH₂OPh— 19004 (CH₃)₃C— o-PhCH₂OPh— 19005 CH₃— m-PhCH₂OPh— 19006 PhCH₂— p-NO₂Ph— 19007 (CH₃)₃C— p-MeOPh— 19008 PhCH₂— p-HOPh— 19009 (CH₃)₃C— Ph— 19010 PhCH₂— p-FPh 19011 PhCH₂— 3-Indolyl- 19012 CH₃— 3-Indolyl- 19013 PhCH₂—

19014 PhCH₂—

19015 (CH₃)₃C— p-PhCH₂OPh— 19016 CH₃CH₂— p-PhCH₂OPh— 19017 PhCH₂— o-PhCH₂OPh— 19018 (CH₃)₃C— m-PhCH₂OPh— 19019 CH₃CH₂— o-PhCH₂OPh— 19020 PhCH₂— p-MeOPh— 19021 (CH₃)₃C— m-MeOPh— 19022 PhCH₂— Ph 19023 PhCH₂— p-CH₃Ph— 19024 (CH₃)₃C— p-ClPh— 19025 (CH₃)₃C— 3-Indolyl- 19026 9-Fluorenylmethyl- 3-Indolyl- 19027 (CH₃)₃C—

19028 9-Fluorenylmethyl-

19029 (CH₃)₃C—

19030 PhCH₂—

19031 (CH3)₂CH—

TABLE 20

Example Compound No. R2— R3— 20001 PhCH₂— p-PhCH₂OPh— 20002 CH₃— p-PhCH₂OPh— 20003 9-Fluorenylmethyl- p-PhCH₂OPh— 20004 (CH₃)₃C— o-PhCH₂OPh— 20005 CH₃— m-PhCH₂OPh— 20006 PhCH₂— p-NO₂Ph— 20007 (CH₃)₃C— p-MeOPh— 20008 PhCH₂— p-HOPh— 20009 (CH₃)₃C— Ph— 20010 PhCH₂— p-FPh 20011 PhCH₂— 3-Indolyl- 20012 CH₃— 3-Indolyl- 20013 PhCH₂—

20014 PhCH₂—

20015 (CH₃)₃C— p-PhCH₂OPh— 20016 CH₃CH₂— p-PhCH₂OPh— 20017 PhCH₂— o-PhCH₂OPh— 20018 (CH₃)₃C— m-PhCH₂OPh— 20019 CH₃CH₂— o-PhCH₂OPh— 20020 PhCH₂— p-MeOPh— 20021 (CH₃)₃C— m-MeOPh— 20022 PhCH₂— Ph 20023 PhCH₂— p-CH₃Ph— 20024 (CH₃)₃C— p-ClPh— 20025 (CH₃)₃C— 3-Indolyl- 20026 9-Fluorenylmethyl- 3-Indolyl- 20027 (CH₃)₃C—

20028 9-Fluorenylmethyl-

20029 (CH₃)₃C—

20030 PhCH₂—

20031 (CH3)₂CH—

TABLE 21

Example Compound No. R2— R3— 21001 PhCH₂— p-PhCH₂OPh— 21002 CH₃— p-PhCH₂OPh— 21003 9-Fluorenylmethyl- p-PhCH₂OPh— 21004 (CH₃)₃C— o-PhCH₂OPh— 21005 CH₃— m-PhCH₂OPh— 21006 PhCH₂— p-NO₂Ph— 21007 (CH₃)₃C— p-MeOPh— 21008 PhCH₂— p-HOPh— 21009 (CH₃)₃C— Ph— 21010 PhCH₂— p-FPh 21011 PhCH₂— 3-Indolyl- 21012 CH₃— 3-Indolyl- 21013 PhCH₂—

21014 PhCH₂—

21015 (CH₃)₃C— p-PhCH₂OPh— 21016 CH₃CH₂— p-PhCH₂OPh— 21017 PhCH₂— o-PhCH₂OPh— 21018 (CH₃)₃C— m-PhCH₂OPh— 21019 CH₃CH₂— o-PhCH₂OPh— 21020 PhCH₂— p-MeOPh— 21021 (CH₃)₃C— m-MeOPh— 21022 PhCH₂— Ph 21023 PhCH₂— p-CH₃Ph— 21024 (CH₃)₃C— p-ClPh— 21025 (CH₃)₃C— 3-Indolyl- 21026 9-Fluorenylmethyl- 3-Indolyl- 21027 (CH₃)₃C—

21028 9-Fluorenylmethyl-

21029 (CH₃)₃C—

21030 PhCH₂—

21031 (CH3)₂CH—

TABLE 22

Example Compound No. R2— R3— 22001 PhCH₂— p-PhCH₂OPh— 22002 CH₃— p-PhCH₂OPh— 22003 9-Fluorenylmethyl- p-PhCH₂OPh— 22004 (CH₃)₃C— o-PhCH₂OPh— 22005 CH₃— m-PhCH₂OPh— 22006 PhCH₂— p-NO₂Ph— 22007 (CH₃)₃C— p-MeOPh— 22008 PhCH₂— p-HOPh— 22009 (CH₃)₃C— Ph— 22010 PhCH₂— p-FPh 22011 PhCH₂— 3-Indolyl- 22012 CH₃— 3-Indolyl- 22013 PhCH₂—

22014 PhCH₂—

22015 H— p-PhCH₂OPh— 22016 CH₃CH₂— p-PhCH₂OPh— 22017 PhCH₂— o-PhCH₂OPh— 22018 (CH₃)₃C— m-PhCH₂OPh— 22019 CH₃CH₂— o-PhCH₂OPh— 22020 PhCH₂— p-MeOPh— 22021 (CH₃)₃C— m-MeOPh— 22022 PhCH₂— Ph 22023 PhCH₂— p-CH₃Ph— 22024 (CH₃)₃C— p-ClPh— 22025 (CH₃)₃C— 3-Indolyl- 22026 9-Fluorenylmethyl- 3-Indolyl- 22027 (CH₃)₃C—

22028 9-Fluorenylmethyl-

22029 (CH₃)₃C—

22030 PhCH₂—

22031 (CH3)₂CH—

TABLE 23

Example Compound No. R2— R3— 23001 PhCH₂— p-PhCH₂OPh— 23002 CH₃— p-PhCH₂OPh— 23003 9-Fluorenylmethyl- p-PhCH₂OPh— 23004 (CH₃)₃C— o-PhCH₂OPh— 23005 CH₃— m-PhCH₂OPh— 23006 PhCH₂— p-NO₂Ph— 23007 (CH₃)₃C— p-MeOPh— 23008 PhCH₂— p-HOPh— 23009 (CH₃)₃C— Ph— 23010 PhCH₂— p-FPh 23011 PhCH₂— 3-Indolyl- 23012 CH₃— 3-Indolyl- 23013 PhCH₂—

23014 PhCH₂—

23015 H— p-PhCH₂OPh— 23016 CH₃CH₂— p-PhCH₂OPh— 23017 PhCH₂— o-PhCH₂OPh— 23018 (CH₃)₃C— m-PhCH₂OPh— 23019 CH₃CH₂— o-PhCH₂OPh— 23020 PhCH₂— p-MeOPh— 23021 (CH₃)₃C— m-MeOPh— 23022 PhCH₂— Ph 23023 PhCH₂— p-CH₃Ph— 23024 (CH₃)₃C— p-ClPh— 23025 (CH₃)₃C— 3-Indolyl- 23026 9-Fluorenylmethyl- 3-Indolyl- 23027 (CH₃)₃C—

23028 9-Fluorenylmethyl-

23029 (CH₃)₃C—

23030 PhCH₂—

23031 (CH3)₂CH—

TABLE 24

Example Compound No. R2— R3— 24001 PhCH₂— p-PhCH₂OPh— 24002 CH₃— p-PhCH₂OPh— 24003 9-Fluorenylmethyl- p-PhCH₂OPh— 24004 (CH₃)₃C— o-PhCH₂OPh— 24005 CH₃— m-PhCH₂OPh— 24006 PhCH₂— p-NO₂Ph— 24007 (CH₃)₃C— p-MeOPh— 24008 PhCH₂— p-HOPh— 24009 (CH₃)₃C— Ph— 24010 PhCH₂— p-FPh 24011 PhCH₂— 3-Indolyl- 24012 CH₃— 3-Indolyl- 24013 PhCH₂—

24014 PhCH₂—

24015 H— p-PhCH₂OPh— 24016 CH₃CH₂— p-PhCH₂OPh— 24017 PhCH₂— o-PhCH₂OPh— 24018 (CH₃)₃C— m-PhCH₂OPh— 24019 CH₃CH₂— o-PhCH₂OPh— 24020 PhCH₂— p-MeOPh— 24021 (CH₃)₃C— m-MeOPh— 24022 PhCH₂— Ph 24023 PhCH₂— p-CH₃Ph— 24024 (CH₃)₃C— p-ClPh— 24025 (CH₃)₃C— 3-Indolyl- 24026 9-Fluorenylmethyl- 3-Indolyl- 24027 (CH₃)₃C—

24028 9-Fluorenylmethyl-

24029 (CH₃)₃C—

24030 PhCH₂—

24031 (CH3)₂CH—

TABLE 25

Example Compound No. R2— R3— 25001 PhCH₂— p-PhCH₂OPh— 25002 CH₃— p-PhCH₂OPh— 25003 9-Fluorenylmethyl- p-PhCH₂OPh— 25004 (CH₃)₃C— o-PhCH₂OPh— 25005 CH₃— m-PhCH₂OPh— 25006 PhCH₂— p-NO₂Ph— 25007 (CH₃)₃C— p-MeOPh— 25008 PhCH₂— p-HOPh— 25009 (CH₃)₃C— Ph— 25010 PhCH₂— p-FPh 25011 PhCH₂— 3-Indolyl- 25012 CH₃— 3-Indolyl- 25013 PhCH₂—

25014 PhCH₂—

25015 H— p-PhCH₂OPh— 25016 CH₃CH₂— p-PhCH₂OPh— 25017 PhCH₂— o-PhCH₂OPh— 25018 (CH₃)₃C— m-PhCH₂OPh— 25019 CH₃CH₂— o-PhCH₂OPh— 25020 PhCH₂— p-MeOPh— 25021 (CH₃)₃C— m-MeOPh— 25022 PhCH₂— Ph 25023 PhCH₂— p-CH₃Ph— 25024 (CH₃)₃C— p-ClPh— 25025 (CH₃)₃C— 3-Indolyl- 25026 9-Fluorenylmethyl- 3-Indolyl- 25027 (CH₃)₃C—

25028 9-Fluorenylmethyl-

25029 (CH₃)₃C—

25030 PhCH₂—

25031 (CH3)₂CH—

TABLE 26

Example Compound No. R2— R3— 26001 PhCH₂— p-PhCH₂OPh— 26002 CH₃— p-PhCH₂OPh— 26003 9-Fluorenylmethyl- p-PhCH₂OPh— 26004 (CH₃)₃C— o-PhCH₂OPh— 26005 CH₃— m-PhCH₂OPh— 26006 PhCH₂— p-NO₂Ph— 26007 (CH₃)₃C— p-MeOPh— 26008 PhCH₂— p-HOPh— 26009 (CH₃)₃C— Ph— 26010 PhCH₂— p-FPh 26011 PhCH₂— 3-Indolyl- 26012 CH₃— 3-Indolyl- 26013 PhCH₂—

26014 PhCH₂—

26015 H— p-PhCH₂OPh— 26016 CH₃CH₂— p-PhCH₂OPh— 26017 PhCH₂— o-PhCH₂OPh— 26018 (CH₃)₃C— m-PhCH₂OPh— 26019 CH₃CH₂— o-PhCH₂OPh— 26020 PhCH₂— p-MeOPh— 26021 (CH₃)₃C— m-MeOPh— 26022 PhCH₂— Ph 26023 PhCH₂— p-CH₃Ph— 26024 (CH₃)₃C— p-ClPh— 26025 (CH₃)₃C— 3-Indolyl- 26026 9-Fluorenylmethyl- 3-Indolyl- 26027 (CH₃)₃C—

26028 9-Fluorenylmethyl-

26029 (CH₃)₃C—

26030 PhCH₂—

26031 (CH3)₂CH—

TABLE 27

Example Compound No. R2— R3— 27001 PhCH₂— p-PhCH₂OPh— 27002 CH₃— p-PhCH₂OPh— 27003 9-Fluorenylmethyl- p-PhCH₂OPh— 27004 (CH₃)₃C— o-PhCH₂OPh— 27005 CH₃— m-PhCH₂OPh— 27006 PhCH₂— p-NO₂Ph— 27007 (CH₃)₃C— p-MeOPh— 27008 PhCH₂— p-HOPh— 27009 (CH₃)₃C— Ph— 27010 PhCH₂— p-FPh 27011 PhCH₂— 3-Indolyl- 27012 CH₃— 3-Indolyl- 27013 PhCH₂—

27014 PhCH₂—

27015 H— p-PhCH₂OPh— 27016 CH₃CH₂— p-PhCH₂OPh— 27017 PhCH₂— o-PhCH₂OPh— 27018 (CH₃)₃C— m-PhCH₂OPh— 27019 CH₃CH₂— o-PhCH₂OPh— 27020 PhCH₂— p-MeOPh— 27021 (CH₃)₃C— m-MeOPh— 27022 PhCH₂— Ph 27023 PhCH₂— p-CH₃Ph— 27024 (CH₃)₃C— p-ClPh— 27025 (CH₃)₃C— 3-Indolyl- 27026 9-Fluorenylmethyl- 3-Indolyl- 27027 (CH₃)₃C—

27028 9-Fluorenylmethyl-

27029 (CH₃)₃C—

27030 PhCH₂—

27031 (CH3)₂CH—

TABLE 28

Example Compound No. R1— R3— 28001 CH₃— p-HOPh— 28002 CH₃— o-HOPh— 28003 CH₃— m-HOPh— 28004 CH₃— p-MeOPh— 28005 CH₃— o-MeOPh— 28006 CH₃— m-MeOPh— 28007 CH₃— p-MePh— 28008 CH₃— p-(CH₃)₂NPh— 28009 CH₃— Ph— 28010 CH₃— p-FPh 28011 CH₃— 3-Indolyl- 28012 CH₃— p-AcNHPh 28013 CH₃—

28014 CH₃—

28015 CH₃—

28016 (CH₃)₂CH— p-HOPh— 28017 (CH₃)₂CH— o-HOPh— 28018 (CH₃)₂CH— m-HOPh— 28019 (CH₃)₂CH— p-MeOPh— 28020 (CH₃)₂CH— o-MeOPh— 28021 (CH₃)₂CH— m-MeOPh— 28022 (CH₃)₂CH— p-MePh— 28023 (CH₃)₂CH— p-(CH₃—)₂NPh— 28024 (CH₃)₂CH— Ph— 28025 (CH₃)₂CH— p-FPh 28026 (CH₃)₂CH— 3-Indolyl- 28027 (CH₃)₂CH— p-AcNHPh 28028 (CH₃)₂CH—

28029 (CH₃)₂CH—

28030 (CH₃)₂CH—

TABLE 29

Example Compound No. R1— R3— 29001 PhCH₂— p-HOPh— 29002 PhCH₂— o-HOPh— 29003 PhCH₂— m-HOPh— 29004 PhCH₂— p-MeOPh— 29005 PhCH₂— o-MeOPh— 29006 PhCH₂— m-MeOPh— 29007 PhCH₂— p-MePh— 29008 PhCH₂— p-(CH₃)₂NPh— 29009 PhCH₂— Ph— 29010 PhCH₂— p-FPh 29011 PhCH₂— 3-Indolyl- 29012 PhCH₂— p-AcNHPh 29013 PhCH₂—

29014 PhCH₂—

29015 PhCH₂—

29016 HOCH₂— p-HOPh— 29017 HOCH₂— o-HOPh— 29018 HOCH₂— m-HOPh— 29019 HOCH₂— p-MeOPh— 29020 HOCH₂— o-MeOPh— 29021 HOCH₂— m-MeOPh— 29022 HOCH₂— p-MePh— 29023 HOCH₂— p-(CH₃)₂NPh— 29024 HOCH₂— Ph— 29025 HOCH₂— p-FPh 29026 HOCH₂— 3-Indolyl- 29027 HOCH₂— p-AcNHPh 29028 HOCH₂—

29029 HOCH₂—

29030 HOCH₂—

TABLE 30

Example Compound No. R1— R3— 30001 CH₃— p-HOPh— 30002 CH₃— o-HOPh— 30003 CH₃— m-HOPh— 30004 CH₃— p-MeOPh— 30005 CH₃— o-MeOPh— 30006 CH₃— m-MeOPh— 30007 CH₃— p-MePh— 30008 CH₃— p-(CH₃)₂NPh— 30009 CH₃— Ph— 30010 CH₃— p-FPh 30011 CH₃— 3-Indolyl- 30012 CH₃— p-AcNHPh 30013 CH₃—

30014 CH₃—

30015 CH₃—

30016 (CH₃)₂CH— p-HOPh— 30017 (CH₃)₂CH— o-HOPh— 30018 (CH₃)₂CH— m-HOPh— 30019 (CH₃)₂CH— p-MeOPh— 30020 (CH₃)₂CH— o-MeOPh— 30021 (CH₃)₂CH— m-MeOPh— 30022 (CH₃)₂CH— p-MePh— 30023 (CH₃)₂CH— p-(CH₃)₂NPh— 30024 (CH₃)₂CH— Ph— 30025 (CH₃)₂CH— p-FPh 30026 (CH₃)₂CH— 3-Indolyl- 30027 (CH₃)₂CH— p-AcNHPh 30028 (CH₃)₂CH—

30029 (CH₃)₂CH—

30030 (CH₃)₂CH—

TABLE 31

Example Compound No. R1— R3— 31001 PhCH₂— p-HOPh— 31002 PhCH₂— o-HOPh— 31003 PhCH₂— m-HOPh— 31004 PhCH₂— p-MeOPh— 31005 PhCH₂— o-MeOPh— 31006 PhCH₂— m-MeOPh— 31007 PhCH₂— p-MePh— 31008 PhCH₂— p-(CH₃)₂NPh— 31009 PhCH₂— Ph— 31010 PhCH₂— p-FPh 31011 PhCH₂— 3-Indolyl- 31012 PhCH₂— p-AcNHPh 31013 PhCH₂—

31014 PhCH₂—

31015 PhCH₂—

31016 HOCH₂— p-HOPh— 31017 HOCH₂— o-HOPh— 31018 HOCH₂— m-HOPh— 31019 HOCH₂— p-MeOPh— 31020 HOCH₂— o-MeOPh— 31021 HOCH₂— m-MeOPh— 31022 HOCH₂— p-MePh— 31023 HOCH₂— p-(CH₃)₂NPh— 31024 HOCH₂— Ph— 31025 HOCH₂— p-FPh 31026 HOCH₂— 3-Indolyl- 31027 HOCH₂— p-AcNHPh 31028 HOCH₂—

31029 HOCH₂—

31030 HOCH₂—

TABLE 32

Example Compound No. R1— R3— 32001 CH₃— p-HOPh— 32002 CH₃— p-PhCH₂OPh— 32003 CH₃— p-MeOCH₂CH₂OPh— 32004 CH₃— p-MeOPh— 32005 CH₃— o-MeOPh— 32006 CH₃— m-MeOPh— 32007 CH₃— p-MePh— 32008 CH₃— p-(CH₃)₂NPh— 32009 CH₃— Ph— 32010 CH₃— p-FPh 32011 CH₃— 3-Indolyl- 32012 CH₃— p-AcNHPh 32013 CH₃—

32014 CH₃—

32015 CH₃—

32016 (CH₃)₂CH— p-HOPh— 32017 (CH₃)₂CH— p-PhCH₂OPh— 32018 (CH₃)₂CH— p-MeOCH₂CH₂OPh— 32019 (CH₃)₂CH— p-MeOPh— 32020 (CH₃)₂CH— o-MeOPh— 32021 (CH₃)₂CH— m-MeOPh— 32022 (CH₃)₂CH— p-MePh— 32023 (CH₃)₂CH— p-(CH₃)₂NPh— 32024 (CH₃)₂CH— Ph— 32025 (CH₃)₂CH— p-FPh 32026 (CH₃)₂CH— 3-Indolyl- 32027 (CH₃)₂CH— p-AcNHPh 32028 (CH₃)₂CH—

32029 (CH₃)₂CH—

32030 (CH₃)₂CH—

TABLE 33

Example Compound No. R1— R3— 33001 PhCH₂— p-HOPh— 33002 PhCH₂— p-PhCH₂OPh— 33003 PhCH₂— p-MeOCH₂CH₂OPh— 33004 PhCH₂— p-MeOPh— 33005 PhCH₂— o-MeOPh— 33006 PhCH₂— m-MeOPh— 33007 PhCH₂— p-MePh— 33008 PhCH₂— p-(CH₃)₂NPh— 33009 PhCH₂— Ph— 33010 PhCH₂— p-FPh 33011 PhCH₂— 3-Indolyl- 33012 PhCH₂— p-AcNHPh 33013 PhCH₂—

33014 PhCH₂—

33015 PhCH₂—

33016 HOCH₂— p-HOPh— 33017 HOCH₂— p-PhCH₂OPh— 33018 HOCH₂— p-MeOCH₂CH₂OPh— 33019 HOCH₂— p-MeOPh— 33020 HOCH₂— o-MeOPh— 33021 HOCH₂— m-MeOPh— 33022 HOCH₂— p-MePh— 33023 HOCH₂— p-(CH₃)₂NPh— 33024 HOCH₂— Ph— 33025 HOCH₂— p-FPh 33026 HOCH₂— 3-Indolyl- 33027 HOCH₂— p-AcNHPh 33028 HOCH₂—

33029 HOCH₂—

33030 HOCH₂—

TABLE 34

Example Compound No. R1— R3— 34001 CH₃— p-HOPh— 34002 CH₃— p-PhCH₂OPh— 34003 CH₃— p-MeOCH₂CH₂OPh— 34004 CH₃— p-MeOPh— 34005 CH₃— o-MeOPh— 34006 CH₃— m-MeOPh— 34007 CH₃— p-MePh— 34008 CH₃— p-(CH₃)₂NPh— 34009 CH₃— Ph— 34010 CH₃— p-FPh 34011 CH₃— 3-Indolyl- 34012 CH₃— p-AcNHPh 34013 CH₃—

34014 CH₃—

34015 CH₃—

34016 (CH₃)₂CH— p-HOPh— 34017 (CH₃)₂CH— p-PhCH₂OPh— 34018 (CH₃)₂CH— p-MeOCH₂CH₂OPh— 34019 (CH₃)₂CH— p-MeOPh— 34020 (CH₃)₂CH— o-MeOPh— 34021 (CH₃)₂CH— m-MeOPh— 34022 (CH₃)₂CH— p-MePh— 34023 (CH₃)₂CH— p-(CH₃)₂NPh— 34024 (CH₃)₂CH— Ph— 34025 (CH₃)₂CH— p-FPh 34026 (CH₃)₂CH— 3-Indolyl- 34027 (CH₃)₂CH— p-AcNHPh 34028 (CH₃)₂CH—

34029 (CH₃)₂CH—

34030 (CH₃)₂CH—

TABLE 35

Example Compound No. R1— R3— 35001 PhCH₂— p-HOPh— 35002 PhCH₂— p-PhCH₂OPh— 35003 PhCH₂— p-MeOCH₂CH₂OPh— 35004 PhCH₂— p-MeOPh— 35005 PhCH₂— o-MeOPh— 35006 PhCH₂— m-MeOPh— 35007 PhCH₂— p-MePh— 35008 PhCH₂— p-(CH₃)₂NPh— 35009 PhCH₂— Ph— 35010 PhCH₂— p-FPh 35011 PhCH₂— 3-Indolyl- 35012 PhCH₂— p-AcNHPh 35013 PhCH₂—

35014 PhCH₂—

35015 PhCH₂—

35016 HOCH₂— p-HOPh— 35017 HOCH₂— p-PhCH₂OPh— 35018 HOCH₂— p-MeOCH₂CH₂OPh— 35019 HOCH₂— p-MeOPh— 35020 HOCH₂— o-MeOPh— 35021 HOCH₂— m-MeOPh— 35022 HOCH₂— p-MePh— 35023 HOCH₂— p-(CH₃)₂NPh— 35024 HOCH₂— Ph— 35025 HOCH₂— p-FPh 35026 HOCH₂— 3-Indolyl- 35027 HOCH₂— p-AcNHPh 35028 HOCH₂—

35029 HOCH₂—

35030 HOCH₂—

TABLE 36

Example Compound No. R1— R3— 36001 CH₃— p-HOPh— 36002 CH₃— p-PhCH₂OPh— 36003 CH₃— p-MeOCH₂CH₂OPh— 36004 CH₃— p-MeOPh— 36005 CH₃— o-MeOPh— 36006 CH₃— m-MeOPh— 36007 CH₃— p-MePh— 36008 CH₃— p-(CH₃)₂NPh— 36009 CH₃— Ph— 36010 CH₃— p-FPh 36011 CH₃— 3-Indolyl- 36012 CH₃— p-AcNHPh 36013 CH₃—

36014 CH₃—

36015 CH₃—

36016 (CH₃)₂CH— p-HOPh— 36017 (CH₃)₂CH— p-PhCH₂OPh— 36018 (CH₃)₂CH— p-MeOCH₂CH₂OPh— 36019 (CH₃)₂CH— p-MeOPh— 36020 (CH₃)₂CH— o-MeOPh— 36021 (CH₃)₂CH— m-MeOPh— 36022 (CH₃)₂CH— p-MePh— 36023 (CH₃)₂CH— p-(CH₃)₂NPh— 36024 (CH₃)₂CH— Ph— 36025 (CH₃)₂CH— p-FPh 36026 (CH₃)₂CH— 3-Indolyl- 36027 (CH₃)₂CH— p-AcNHPh 36028 (CH₃)₂CH—

36029 (CH₃)₂CH—

36030 (CH₃)₂CH—

TABLE 37

Example Compound No. R1— R3— 37001 PhCH₂— p-HOPh— 37002 PhCH₂— p-PhCH₂OPh— 37003 PhCH₂— p-MeOCH₂CH₂OPh— 37004 PhCH₂— p-MeOPh— 37005 PhCH₂— o-MeOPh— 37006 PhCH₂— m-MeOPh— 37007 PhCH₂— p-MePh— 37008 PhCH₂— p-(CH₃)₂NPh— 37009 PhCH₂— Ph— 37010 PhCH₂— p-FPh 37011 PhCH₂— 3-Indolyl- 37012 PhCH₂— p-AcNHPh 37013 PhCH₂—

37014 PhCH₂—

37015 PhCH₂—

37016 HOCH₂— p-HOPh— 37017 HOCH₂— p-PhCH₂OPh— 37018 HOCH₂— p-MeOCH₂CH₂OPh— 37019 HOCH₂— p-MeOPh— 37020 HOCH₂— o-MeOPh— 37021 HOCH₂— m-MeOPh— 37022 HOCH₂— p-MePh— 37023 HOCH₂— p-(CH₃)₂NPh— 37024 HOCH₂— Ph— 37025 HOCH₂— p-FPh 37026 HOCH₂— 3-Indolyl- 37027 HOCH₂— p-AcNHPh 37028 HOCH₂—

37029 HOCH₂—

37030 HOCH₂—

TABLE 38

Example Compound No. R1— R3— 38001 CH₃— p-HOPh— 38002 CH₃— p-PhCH₂OPh— 38003 CH₃— p-MeOCH₂CH₂OPh— 38004 CH₃— p-MeOPh— 38005 CH₃— o-MeOPh— 38006 CH₃— m-MeOPh— 38007 CH₃— p-MePh— 38008 CH₃— p-(CH₃)₂NPh— 38009 CH₃— Ph— 38010 CH₃— p-FPh 38011 CH₃— 3-Indolyl- 38012 CH₃— p-AcNHPh 38013 CH₃—

38014 CH₃—

38015 CH₃—

38016 (CH₃)₂CH— p-HOPh— 38017 (CH₃)₂CH— p-PhCH₂OPh— 38018 (CH₃)₂CH— p-MeOCH₂CH₂OPh— 38019 (CH₃)₂CH— p-MeOPh— 38020 (CH₃)₂CH— o-MeOPh— 38021 (CH₃)₂CH— m-MeOPh— 38022 (CH₃)₂CH— p-MePh— 38023 (CH₃)₂CH— p-(CH₃)₂NPh— 38024 (CH₃)₂CH— Ph— 38025 (CH₃)₂CH— p-FPh 38026 (CH₃)₂CH— 3-Indolyl- 38027 (CH₃)₂CH— p-AcNHPh 38028 (CH₃)₂CH—

38029 (CH₃)₂CH—

38030 (CH₃)₂CH—

TABLE 39

Example Compound No. R1— R3— 39001 PhCH₂— p-HOPh— 39002 PhCH₂— p-PhCH₂OPh— 39003 PhOH₂— p-MeOCH₂CH₂OPh— 39004 PhCH₂— p-MeOPh— 39005 PhCH₂— o-MeOPh— 39006 PhCH₂— m-MeOPh— 39007 PhCH₂— p-MePh— 39008 PhCH₂— p-(CH₃)₂NPh— 39009 PhCH₂— Ph— 39010 PhCH₂— p-FPh 39011 PhCH₂— 3-Indolyl- 39012 PhCH₂— p-AcNHPh 39013 PhCH₂—

39014 PhCH₂—

39015 PhCH₂—

39016 HOCH₂— p-HOPh— 39017 HOCH₂— p-PhCH₂OPh— 39018 HOCH₂— p-MeOCH₂CH₂OPh— 39019 HOCH₂— p-MeOPh— 39020 HOCH₂— o-MeOPh— 39021 HOCH₂— m-MeOPh— 39022 HOCH₂— p-MePh— 39023 HOCH₂— p-(CH₃)₂NPh— 39024 HOCH₂— Ph— 39025 HOCH₂— p-FPh 39026 HOCH₂— 3-Indolyl- 39027 HOCH₂— p-AcNHPh 39028 HOCH₂—

39029 HOCH₂—

39030 HOCH₂—

There will be described representative preparation processes according to this invention.

In a process for preparing a compound represented by general formula (5) or (6) from a compound represented by general formula (1) as a starting material in this invention, the meaning of the phrase “configuration of R¹ attached to the carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (5) is erythro” may be described in the following reaction equations 1 and 2 in detail:

Specifically, as shown in reaction equation 1, S-form optically active 5-oxazolidinone derivative represented by general formula (9) selectively gives a 1R,2S-optically active aminoalcohol derivative of erythro configuration represented by general formula (12) or (13). Furthermore, as shown in reaction formula 2, an R-form optically active 5-oxazolidinone derivative represented by general formula (14) can provide a 1S,2R-optically active aminoalcohol derivative of erythro configuration represented by general formula (17) or (18).

Each preparation step will be detailed.

Preparation of an Optically Active 5-Oxazolidinone Derivative Represented by General Formula (1)

An optically active 5-oxazolidinone derivative represented by general formula (1) can be provided according to a well-known process where an N-urethane protected compound derived from a readily available and inexpensive natural α-amino acid is reacted with paraformaldehyde in the presence of a catalytic amount of an acid (J. Am. Chem. Soc. 1957, 79, 5736).

Preparation of an Organometallic Reagent Represented by General Formula (2)

An organometallic reagent represented by general formula (2) may be easily prepared by a well-known process; for example, oxidative addition of a metal to a corresponding halogenated compound or transmetallation with an organometallic reagent.

In preparation of an organometallic reagent, there is no limitation of the solvent, as long as it is inert to the reaction, and, for example, ethers such as tetrahydrofuran, diethyl ether, dioxane and diglyme; toluene; and xylenes can be used. Among these, preferred is tetrahydrofuran alone or a mixture of tetrahydrofuran and another solvent in the light of solubility of a substrate. A reaction temperature may be generally −78° C. to a boiling point of the solvent used. Furthermore, an organometallic reagent, particularly a Grignard reagent can be used to give good results in a preparation process according to this invention.

A Grignard reagent may be easily prepared by, for example, adding dropwise a halogenated compound represented by R³X where X is as defined above, after initiating the reaction by adding a catalytic amount of an initiator such as 1,2-dibromoethane, ethyl bromide and iodine to magnesium dispersed in a solvent.

Preparation of an Optically Active 5-Hydroxyoxazolidine Derivative Represented by General Formula (3)

In a reaction of an optically active 5-oxazolidinone derivative represented by general formula (1) with an organometallic reagent represented by general formula (2), a reaction solvent may be, but not limited to, the same solvent as that used in preparing the organometallic reagent or a solvent mixture which does not significantly affect the reaction. The amount of the organometallic reagent is preferably, but not limited to, an equal to a five-fold moles, more preferably 1.0 to 2-fold moles per one mole of the 5-oxazolidinone derivative as a substrate. A reaction temperature may be preferably, but not limited to, an ambient temperature, room temperature, to −78° C. In this reaction, there are no restrictions to the order of adding the optically active 5-oxazolidinone derivative and the organometallic reagent. That is, the organometallic reagent may be added to the optically active 5-oxazolidinone derivative or vice versa. At the end of the reaction, for obtaining the optically active 5-hydroxyoxazolidine derivative produced, the excessive organometallic reagent in the reaction solution is decomposed using, for example, an aqueous diluted hydrochloric acid, diluted sulfuric acid, acetic acid, ammonium chloride, citric acid or potassium hydrogen sulfate solution and then the product can be isolated from the resulting mixture by a common separation/purification process such as extraction, concentration, neutralization, filtration, recrystallization and column chromatography.

Furthermore, as described above, a Grignard reagent can be used as an organometallic reagent to give particularly good results in this reaction. When using a Grignard reagent as an organometallic reagent, the conditions including a reaction solvent, the amount of the materials used, a reaction temperature, the order of adding the reagents, work-up of the reaction and isolation and purification of the product are as described for the above general preparation process when using an organometallic reagent.

The optically active 5-oxazolidine derivative prepared as described above is generally obtained as a mixture of two diastereomers because both R- and S-forms are formed for configuration at the 5-position in the oxazolidine. Depending on the conditions, high performance liquid chromatography or nuclear magnetic spectrometry may be performed to determine a diastereomer ratio. A diastereomer ratio may vary depending on the reaction conditions and properties of the product, and the diastereomers may be individually isolated or may be obtained as a mixture. However, a diastereomer mixture may be converted into an optically active aminoketone derivative represented by the same general formula (4) by, for example, treatment with an acid described below. It is, therefore, not necessary to separate the diastereomers as production intermediates in the light of a production cost.

Preparation of an Optically Active Aminoketone Derivative Represented by General Formula (4)

A process for converting an optically active 5-hydroxyoxazolidine derivative into an optically active aminoketone derivative represented by general formula (4) under an acidic condition can be generally conducted in a solvent. Examples of a solvent which can be used include, but not limited to, alcohols such as methanol and ethanol; acetonitrile; tetrahydrofuran; benzene; toluene; and water. These solvents may be used alone or in combination of two or more in a given mixing ratio. Examples of an acid which can be used include, but not limited to, inorganic acids such as hydrochloric acid, sulfuric acid and perchloric acid; organic acids such as p-toluenesulfonic acid and methanesulfonic acid; acidic resins such as Amberlite IR-120 and Amberlist; and Lewis acids such as boron trifluoride and zinc chloride. The amount of an acid used is an equal to 30-fold moles, preferably 1.5- to 10-fold moles per one mole of the optically active 5-hydroxyoxazolidine derivative. When using a resin, its amount is 5 to 200% by weight, preferably 10 to 100% by weight. A reaction temperature may be −30° C. to a boiling point of a solvent, particularly 0° C. to 100° C. An aminoketone derivative may be easily isolated from a reaction mixture by a common separation/purification method such as extraction, concentration, neutralization, filtration, recrystallization and column chromatography.

Preparation of an Optically Active Aminoalcohol Derivative Represented by General Formula (5)

A process for reducing an aminoketone derivative represented by general formula (4) with a reducing agent to give an optically active alcohol derivative represented by general formula (5) is generally conducted in a solvent. Examples of the solvent, which can be used include, but not limited to, methanol, ethanol, 2-propanol, tetrahydrofuran and water. These solvents may be used alone or in combination of two or more in a given mixing ratio.

Examples of the reducing agent include borane reagents such as borane-tetrahydrofuran complex; borohydride reagents such as sodium borohydride, zinc borohydride and sodium trimethoxyborohydride; alkylaluminum reagents such as diisopropylaluminum hydride; aluminum hydride reagents such as lithium aluminum hydride and lithium trialkoxyaluminum hydride; silane reagents such as trichlorosilane and triethylsilane; sodium metal in liquid ammonia; and magnesium metal in an alcohol. In particular, borohydride reagents such as sodium borohydride, zinc borohydride and sodium trimethoxyborohydride are suitable.

The amount of the reducing agent may be an equal to 10-fold moles per one mole of a material to be reduced. A reaction temperature is appropriately selected within the range of −78° C. to a boiling point of the solvent, preferably −40° C. to 80° C.

Alternatively, an aminoketone derivative represented by general formula (4) may be catalytically hydrogenated in the presence of an appropriate metal catalyst in an appropriate solvent under an atmosphere of hydrogen, to give an optically active aminoalcohol derivative represented by general formula (5). A hydrogen pressure may be, but not limited to, an ambient pressure to 3 MPa, preferably 0.3 MPa to 1 MPa. Any solvent may be used as long as it does not adversely affect the reaction; for example, methanol, ethanol, n-propanol, 2-propanol, n-butanol and water. These solvents may be used alone or in combination of two or more in a given mixing ratio. The amount of a solvent is 1 to 50 parts (wt/wt), preferably 3 to 20 parts per one part of the compounds.

Examples of the metal catalyst which can be used include nickel catalysts such as Raney nickel; platinum catalysts such as platinum-alumina, platinum-carbon and platinum oxide; palladium catalysts such as palladium-alumina, palladium-carbon and palladium hydroxide-carbon; ruthenium catalysts such as ruthenium oxide; and rhodium catalysts such as chlorotris(triphenylphosphine)rhodium which is also known as a Wilkinson catalyst, more suitably palladium catalysts. A reaction temperature may be, but not limited to, −20 to 200° C., preferably 0 to 60° C.

A process for deprotecting a compound represented by general formula (5) having a protected amino group as appropriate to give a free amine derivative represented by general formula (6) may be conducted by, for example, hydrolysis using an acid or base. Examples of an acid, which can be used include, but not limited to, inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; and organic acids such as trifluoromethanesulfonic acid, is trifluoroacetic acid, p-toluenesulfonic acid and acetic acid. Examples of a base, which can be used, include inorganic bases such as sodium hydrogen carbonate, potassium carbonate, lithium hydroxide and sodium hydroxide; and organic bases such as triethylamine, morpholine, tetrabutylammonium fluoride and tetraethylammonium hydroxide.

An optically active aminoalcohol derivative represented by general formula (5) or (6) thus obtained may be isolated as crystals of the free amine or as a salt by adding, if necessary, an appropriate acid. A diastereomeric purity or optical purity of the compound may be improved by recrystallization.

When the compound is obtained as crystals of a free amine, any solvent which is suitable to such purification can be used for crystallization. Examples of such a solvent include alcohols such as methanol, ethanol, n-propanol and 2-propanol; esters such as ethyl acetate and butyl acetate; halogenated solvents such as chloroform and methylene chloride; ethers such as 1,4-dioxane and tetrahydrofuran; water; acetonitrile; 2-butanone; and toluene, which can be used alone or in combination of two or more.

Any acid which can form a crystalline salt suitable for purification may be used for salt formation. Examples of such an acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, methanesulfonate and p-toluenesulfonate.

Any solvent which is suitable for purification may be used for recrystallization. Examples of such solvent include alcohols such as methanol, ethanol, n-propanol and 2-propanol; esters such as ethyl acetate and butyl acetate; halogenated solvents such as chloroform and methylene chloride; ethers such as 1,4-dioxane and tetrahydrofuran; water; acetonitrile; 2-butanone; and toluene, which may be used alone or in combination of two or more.

A salt purified by recrystallization may be treated with an alkaline solution by a common procedure to be isolated as a free amine.

EXAMPLES

This invention will be more specifically described with reference to, but not limited to, Reference Examples and Examples.

Reference Example 1

Preparation of (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone

Benzyloxycarbonyl-L-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g) were suspended in toluene (190 mL), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the reaction mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and then saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, the resulting crystals were filtrated to give the title compound (19.0 g) as white crystals in an yield of 93%.

Melting point: 91–93° C. ¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.54 (d, 3H, J=6.4 Hz), 4.29–4.31 (m, 1H), 5.18 (s, 2H), 5.28–5.29 (m, 1H), 5.47 (br, 1H), 7.33–7.41 (m, 5H); IR (KBr) ν_(max) 1778, 1685 cm⁻¹.

Reference Example 2

Preparation of 4-benzyloxybromobenzene

p-Bromophenol (25.0 g) and anhydrous potassium carbonate (20.0 g) were suspended in N,N-dimethylformamide (250 mL). To the suspension was added dropwise benzyl chloride (20.2 g) at room temperature. After heating at 95 to 100° C. for one hour, the reaction mixture was cooled to room temperature and water (400 mL) was added. After extraction with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (34.3 g) as milk-white crystals in a yield of 90%.

Melting point: 55–57° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 5.04 (s, 2H), 6.83–6.87 (m, 2H), 7.31–7.43 (m, 2H).

Example 1

Preparation of (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (Compound No. 1001)

Preparation of a Grignard Reagent

To magnesium metal (1.16 g) in anhydrous tetrahydrofuran (20 mL) was added ethyl bromide (0.26 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. At reflux of the solvent, a solution of 4-benzyloxybromobenzene (10.5 g) prepared in Reference Example 2 dissolved in anhydrous tetrahydrofuran (20 mL) was added dropwise over about 1 hour. At the end of addition, the mixture was stirred at reflux for further 40 min to prepare a Grignard reagent.

Grignard Reaction

In anhydrous tetrahydrofuran (40 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.84 g) prepared in Reference Example 1 and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent prepared above while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred for further 1 hour at that temperature, and then treated with an aqueous 5% hydrochloric acid solution. The solution was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (9.85 g) as a diastereomer mixture as white crystals in a yield of 71%.

Melting point: 83–86° C. ¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio was about 2:1.

Major Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.47 (d, 3H, J=7.3 Hz), 3.81–3.84 (m, 1H), 4.79–5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20 (d, 1H, J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 8.01 (d, 2H, J=8.8 Hz)

Sub Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.49 (d, 3H, J=7.3 Hz), 3.60–3.70 (m, 1H), 4.79–5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 7.83 (d, 2H, J=8.8 Hz); IR (neat) ν_(max) 3436, 3033, 1671, 1603, 1508 cm⁻¹.

Example 2

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (Compound No.: 22001)

In toluene (50 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (3.8 g) prepared in Example 1. After adding Amberlist (300 mg), the mixture was reacted at room temperature. At the end of the reaction, Amberlist was filtered off, the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (3.1 g) as pale yellow crystals in a yield of 88%.

Melting point: 89–91° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.83 Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28–5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31–7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz); IR (KBr) ν_(max) 3374, 1712, 1690 cm⁻¹;

Optical purity: 93%ee

HPLC Analysis Conditions:

-   -   Column: Daicel Chiral-Pak AD-RH (4.6 mmφ×150 mm);     -   Mobile phase: methanol;     -   Flow rate: 0.5 mL/min;     -   Wavelength: 254 nm;     -   Temperature: room temperature;     -   t_(R): (2S-form); 19.8 min;         -   (2R-form); 24.3 min.

Example 3

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (Compound No. 22001)

Preparation of a Grignard Reagent

To anhydrous tetrahydrofuran (15 mL) under nitrogen atmosphere were added magnesium metal (1.16 g) and ethyl bromide (0.05 g), and the mixture was stirred at room temperature for 30 min. To the mixture at reflux of the solvent was added dropwise a solution of 4-benzyloxybromobenzene (10.92 g) prepared in Reference Example 2 dissolved in anhydrous tetrahydrofuran (10 mL) over about 1 hour. At the end of addition, the mixture was stirred at reflux for further 30 min to prepare a Grignard reagent.

Grignard Reaction

In anhydrous tetrahydrofuran (26 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (6.97 g) prepared in Reference Example 1 and the mixture was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent prepared above while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred for further 1 hour at that temperature.

Deformylation

To the mixture was added a 6.5% aqueous hydrochloric acid solution, and the reaction was stirred at 35 to 40° C. for 6 hours. The aqueous layer was discarded after separation. Then to the organic layer was added a 5% aqueous hydrochloric acid solution, and the mixture was stirred at 45 to 50° C. for 4 hours. The reaction mixture was extracted with toluene and the organic layer was washed with water. The solution was concentrated in vacuo, 2-propanol (70 g) was added, and then the mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0 to 5° C. to precipitate crystals, which were then filtered to give the title compound (8.61 g) as pale yellow crystals in a yield of 80%.

Melting point: 89–91° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.8 Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28–5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31–7.44 (m, 10H), 7.96 (d, 2H, J=9.3 Hz); IR (KBr) ν_(max) 3374, 1712, 1690 cm⁻¹; Specific rotation: [α]^(D) ₂₄=+26° (C=1.00, CHCl₃) Optical purity: 99%ee (analytical conditions are as described in Example 2).

Example 4

Preparation of erythro-(1R,2S)-p-hydroxynorephedrine (Compound No. 28001)

A mixture of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (4.8 g) prepared in Example 2 or 3, methanol (100 mL), water (50 mL) and 5% Pd/C (50% water-containing) (1.0 g) was stirred below 20° C. under hydrogen atmosphere (0.5 MPa) for 28 hours. The catalyst was filtered off, the filtrate was concentrated in vacuo, and the residue was slushed with 2-propanol to give the title compound (1.44 g) as white crystals in a yield of 70%.

Melting point: 163–165° C.; ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.3 Hz), 2.77–2.83 (m, 1H), 4.17 (d, 1H, J=5.3 Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, J=8.3 Hz), 8.31 (s, 1H); IR (KBr) ν_(max) 3470, 1593, 1484, 1242 cm⁻¹; Specific rotation: [α]^(D) ₂₄=−18° (C=0.2, MeOH);

Erythro:threo=99.5:0.5;

HPLC Analysis Conditions:

-   -   Column: YMC TMS A-102 (6 mmφ×150 mm)     -   Mobile phase: acetonitrile:water=3:97 (each of NaH₂PO₄ and         Na₂HPO₄ is 10 mM, pH 6.9);     -   Detection wavelength: 275 nm;     -   Flow rate: 0.5 mL/min;     -   Column temperature: 40° C.;     -   t_(R): erythro form; 6.9 min;         -   threo form; 7.1 min;     -   Optical purity: 99%ee         HPLC Analysis Conditions:     -   Column: Daicel Crown-Pak CR(−) (4 mmφ×150 mm);     -   Mobile phase: HClO₄ aq (pH 3.5);     -   Detection wavelength: 275 nm;     -   Flow rate: 0.1 mL/min;     -   Column temperature: 25° C.

Example 5

Preparation of erythro-(1R,2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanol (Compound No.: 36002)

To methanol (25 mL) was added sodium borohydride (0.32 g), and the mixture was cooled to 0 to 5° C. To the solution was added (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (2.00 g) prepared in Example 2 or 3, and the mixture was stirred at room temperature. Precipitated crystals were filtered, washed with methanol and then dried to give the title compound (1.39 g) as white crystals in a yield of 69%.

Melting point: 85–91° C.; ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm: 0.99 (d, 3H, J=6.59 Hz), 3.61–3.62 (m, 1H), 4.46–4.49 (m, 1H), 4.95 (s, 2H), 5.07 (s, 2H), 5.23 (m, 1H), 6.93 (d, 2H, J=7.08), 7.19–7.40 (m, 10H), 7.44 (d, 2H, J=7.08), 8.30 (s, 1H); IR (KBr) ν_(max) 3334, 1690 cm⁻¹.

Example 6

Preparation of erythro-(1R,2S)-p-hydroxynorephedrine (Compound No.: 28001)

In methanol was dissolved erythro-(1R,2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanol (1.39 g) prepared in Example 5, and the solution was stirred with 5% Pd/C (50% water-containing) (0.03 g) under hydrogen atmosphere (ambient pressure) at room temperature for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated in vacuo. The residue was crystallized with 2-propanol to give the title compound (0.65 g) as white crystals in a yield of 75%.

Melting point: 163–165° C.; ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.3 Hz), 2.77–2.83 (m, 1H), 4.17 (d, 1H, J=5.3 Hz), 4.96 (brs, 1H), 6.70 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, J=8.3 Hz), 8.31 (s, 1H); IR (KBr) ν_(max) 3470, 1593, 1484, 1242 cm⁻¹; Specific rotation: [α]^(D) ₂₄=−18° (C=0.2, MeOH); Erythro:threo=97.5:2.5 (analysis conditions are as described in Example 4);

Optical purity: 99%ee (analysis conditions are as described in Example 4).

Reference Example 3

Preparation of (4S)-N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone

In toluene (250 mL) were suspended tert-butoxycarbonyl-L-alanine (18.9 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the crystals obtained were filtered to give the title compound (14.2 g) white crystals in a yield of 71%.

Melting point: 66–68° C.; ¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.49 (s, 9H), 1.52 (d, 2H, J=7.1 Hz), 4.23 (br, 1H), 5.23 (br, 1H), 5.41 (br, 1H); IR (KBr) ν_(max) 1798, 1698 cm⁻¹.

Example 7

Preparation of (4S)-5-(4-benzyloxyphenyl)-N-tert-butoxycarbonyl-4-methyl-5-hydroxyoxazolidine (Compound No.: 1015)

In anhydrous tetrahydrofuran (40 mL) was dissolved (4S)-N-tert-butoxycarbonyl-4-methyl-5-oxazolidinone (6.64 g) prepared in Reference Example 3, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise a Grignard reagent prepared as described in Example 1 while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred at that temperature for 1 hour and then treated with a 5% aqueous hydrochloric acid solution. The solution was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo and the residue was purified by silica column chromatography (eluent: chloroform) to give the title compound (10.2 g) as a diastereomer mixture as a pale yellow syrup in an yield of 80%.

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.35–1.38 (m, 3H), 1.44–1.49 (m, 9H), 4.90–5.85 (m, 5H), 6.99–7.03 (m, 2H), 7.35–7.44 (m, 5H), 7.80–8.00 (m, 2H); IR (KBr) ν_(max) 3422, 1683 cm⁻¹.

Reference Example 4

Preparation of (4S)-N-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone

In toluene (250 mL) were suspended benzyloxycarbonyl-L-valine (25.1 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give the title compound (23.7 g) as colorless transparent syrup in an yield of 90%.

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.00 (d, 3H, J=6.6 Hz), 1.07 (d, 3H, J=6.6 Hz), 2.30–2.40 (m, 1H), 4.22 (bs, 1H), 5.15–5.22 (m, 3H), 5.56 (bs, 1H), 7.15–7.40 (m, 5H); IR (KBr) ν_(max) 1798, 1698 cm⁻¹.

Example 8

Preparation of (4S)-5-(4-benzyloxyphenyl)-N-benzyloxycarbonyl-4-isopropyl-5-hydroxyoxazolidine (Compound No.: 2001)

In anhydrous tetrahydrofuran (22 mL) was dissolved (4S)-benzyloxycarbonyl-4-isopropyl-5-oxazolidinone (5.20 g) prepared in Reference Example 4, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise a Grignard reagent prepared as described in Example 1 while maintaining the internal temperature at −10 to 20° C. At the end of addition, the mixture was stirred at that temperature for 1 hour and then treated with a 12.5% aqueous hydrochloric acid solution. The solution was warmed to room temperature, extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (4.72 g) as a diastereomer mixture as a pale yellow syrup in an yield of 53%.

¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio was about 1.9:1.

Major Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 0.85 (d, 3H, J=6.6 Hz), 0.98 (d, 2H, J=6.6), 2.29–2.40 (m, 1H), 3.29 (m, 1H), 4.79 (m, 1H), 5.10–5.50 (m, 6H), 7.02 (d, 2H, J=8.7 Hz), 7.28–7.45 (m, 10H), 8.11 (d, 2H, J=8.7 Hz);

Sub Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 0.83 (d, 3H, J=6.2 Hz), 1.00 (d, 2H, J=6.2), 2.29–2.40 (m, 1H), 3.55 (m, 1H), 4.79 (m, 1H), 5.10–5.50 (m, 6H), 6.81 (d, 2H, J=9.0 Hz), 7.28–7.45 (m, 10H), 7.85 (d, 2H, J=9.0 Hz); IR (KBr) ν_(max) 3422, 1683 cm⁻¹

Example 9

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-3-methyl-1-butanone (Compound No.: 23001)

In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-isopropyl-5-hydroxyoxazolidine (1.38 g) prepared in Example 8, and to the solution were added water (5 mL) and conc. hydrochloric acid (2 mL). The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene and the aqueous layer was discarded. The organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (466 mg) as pale yellow crystals in a yield of 36%.

Melting point: 75–77° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 0.76 (d, 3H, J=6.8 Hz), 1.04 (d, 3H, J=6.8 Hz), 2.16 (m, 1H), 5.11 (s, 1H), 5.14 (s, 1H), 5.24 (dd, 1H, J=8.8, 4 Hz), 5.70 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz), 7.30–7.45 (m, 10H), 7.96 (d, 2H, J=8.8 Hz); IR (KBr) ν_(max) 3422, 1683 cm⁻¹.

Example 10

Preparation of (4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 1020)

Preparation of a Grignard Reagent

To anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere were added magnesium metal (756 mg) and ethyl bromide (0.1 g), and the mixture was stirred at room temperature for 1 hour. To the mixture at reflux of the solvent was added dropwise a solution of 4-bromoanisole (3.76 g) dissolved in anhydrous tetrahydrofuran (20 mL) over 1 hour. At the end of addition, the mixture was stirred at reflux for further 40 min to prepare a Grignard reagent.

Grignard Reaction

In anhydrous tetrahydrofuran (30 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (7.70 g) prepared in Reference Example 1, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred for 1 hour at that temperature and then treated with a 5% aqueous hydrochloric acid solution. The solution was warmed to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1 to 3/2), to give the title compound (4.56 g) as a diastereomer mixture as a colorless transparent syrup in a yield of 66%.

¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio was about 2:1.

Major Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.47 (d, 3H, J=7 Hz), 3.70–3.75 (m, 1H), 3.87 (s, 3H), 4.80–5.20 (m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d, 1H, J=12.4 Hz), 5.88 (q, 1H, J=7 Hz), 6.95 (d, 2H, J=9.0 Hz), 7.23–7.36 (m, 5H), 8.02 (d, 2H, J=9.0 Hz);

Minor Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.48 (d, 3H, J=7 Hz), 3.70–3.75 (m, 1H), 3.86 (s, 3H), 4.80–5.20 (m, 2H), 5.16 (d, 1H, J=12.4 Hz), 5.25 (d, 1H, J=12.4 Hz), 5.57 (q, 1H, J=7 Hz), 6.83 (d, 2H, J=8.8 Hz), 7.23–7.36 (m, 5H), 8.83 (d, 2H, J=8.8 Hz) IR (neat) ν_(max) 3443, 1697, 1601 cm⁻¹.

Example 11

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(4-methoxyphenyl)-1-propanone (Compound No.: 22020)

In tetrahydrofuran (4 mL) was dissolved (4S)-N-benzyloxycarbonyl-5-(4-methoxyphenyl)-4-methyl-5-hydroxyoxazolidine (1.72 g) prepared in Example 10 and then water (5 mL) and conc. hydrochloric acid (2 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with toluene, the aqueous layer was discarded, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under a reduced pressure, the residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (1.40 mg) as white crystals in a yield of 89%.

Melting point: 46–48° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.8 Hz), 3.88 (s, 3H), 5.13 (s, 2H), 5.30 (dq, 1H, J=7.1, 6.8 Hz), 5.91 (d, 1H, J=7.1 Hz), 6.96 (d, 2H, J=8.8 Hz), 7.29–7.37 (m, 5H), 7.96 (d, 2H, J=8.8 Hz); IR (KBr) ν_(max) 3458, 2958, 1714, 1676, 1597, 1527 cm⁻¹.

Example 12

Preparation of (4S)-N-benzyloxycarbonyl-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 1030)

Preparation of a Grignard Reagent

To anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere were added magnesium metal (2.56 g) and iodine (30 mg). To the mixture at room temperature was added one-fifth of a solution of 2,4-difluorobromobenzene (19.3 g) dissolved in anhydrous tetrahydrofuran (60 mL) in one portion. Five minutes after addition, Grignard reagent formation was initiated as indicated by temperature rising of the reaction. While maintaining a reaction temperature below 45° C., the remaining four-fifths of the reagent was added dropwise over about 30 min. At the end of addition, the mixture was stirred at 25 to 40° C. for 30 min to give a Grignard reagent.

Grignard Reaction

In anhydrous tetrahydrofuran (68 mL) was dissolved (4S)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (21.2 g) prepared in Reference Example 1, and the solution was cooled to −20° C. To the solution under nitrogen atmosphere was added dropwise the Grignard reagent prepared while maintaining the internal temperature at −20° C. At the end of addition, the mixture was stirred at that temperature for one hour and treated with a 5% aqueous hydrochloric acid solution. The solution was warmed to room temperature and extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=2/1) to give the title compound (21.4 g) as a diastereomer mixture as a pale yellow syrup in a yield of 68%.

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.52 and 1.51 (2d, 3H, J=6.8 Hz), 3.20–3.45 (m, 1H), 4.30–4.50 (m, 1H), 4.70–5.45 (m, 4H), 6.55–6.90 (m, 2H), 7.30–7.40 (m, 5H), 7.50–7.90 (m, 1H); IR (KBr) ν_(max) 3402, 1803, 1701, 1614 cm⁻¹.

Example 13

Preparation of (2S)-2-(benzyloxycarbonyl)amino-1-(2,4-difluorophenyl)-1-propanone (Compound No.: 22030)

In tetrahydrofuran (70 mL) was dissolved (4S)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (14.0 g) prepared in Example 12, and water (50 mL) and conc. hydrochloric acid (20 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (11.7 g) as a pale yellow syrup in a yield of 92%.

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.40 (d, 3H, J=7.0 Hz), 5.10 (s, 2H), 5.05–5.20 (m, 1H), 5.75–5.80 (m, 1H), 6.88–6.94 (m, 1H), 6.98–7.02 (m, 1H), 7.30–7.37 (m, 5H), 7.95–8.01 (m, 1H); IR (neat) ν_(max) 3358, 1718, 1681, 1611, 1532 cm⁻¹, Optical purity: 90%ee;

HPLC Analysis Conditions

-   -   Column: Daicel Chiral-Pak AD-RH (4.6 mmφ×150 mm);     -   Mobile phase: methanol;     -   Flow rate: 0.5 mL/min;     -   Wavelength: 254 nm;     -   Temperature: room temperature;     -   t_(R): (2R-form); 6.5 min         -   (2S-form); 7.5 min.

Reference Example 5

Preparation of (4R)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone

In toluene (190 mL) were suspended benzyloxycarbonyl-D-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The precipitated crystals were filtered to give the title compound (17.4 g) as white crystals in a yield of 85%.

Melting point: 89–91° C.; ¹H NMR (CDCl₃, 400 MHz) δ ppm: 1.54 (d, 3H, J=6.4 Hz), 4.29–4.31 (m, 1H), 5.18 (s, 2H), 5.28–5.29 (m, 1H), 5.47 (br, 1H), 7.33–7.41 (m, 5H); IR (KBr) ν_(max) 1778, 1685 cm⁻¹.

Example 14

Preparation of (4R)-N-benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 19001)

(4R)-N-Benzyloxycarbonyl-4-methyl-5-oxazolidinone (2.61 g) prepared in Reference Example 5 was processed as described in Example 1 to give the title compound (9.0 g) as a diastereomer mixture as white crystals in an yield of 65%.

Melting point: 82–86° C. ¹H-NMR (CDCl₃, 400 MHz) indicated that a diastereomer ratio was about 2:1.

Major Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.47 (d, 3H, J=7.3 Hz), 3.81–3.84 (m, 1H), 4.79–5.07 (m, 2H), 5.14 (s, 2H), 5.14 (d, 1H, J=8.4 Hz), 5.20 (d, 1H, J=8.4 Hz), 5.87 (q, 1H, J=7.3 Hz), 7.02 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 8.01 (d, 2H, J=8.8 Hz);

Sub Diastereomer Product

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.49 (d, 3H, J=7.3 Hz), 3.60–3.70 (m, 1H), 4.79–5.15 (m, 4H), 5.13 (s, 2H), 5.57 (q, 1H, J=7.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.23–7.44 (m, 10H), 7.83 (d, 2H, J=8.8 Hz); IR (neat) ν_(max) 3436, 3033, 1671, 1603, 1508 cm⁻¹.

Example 15

Preparation of (2R)-2-(benzyloxycarbonyl)amino-1-(4-benzyloxyphenyl)-1-propanone (Compound No. 25001)

(4R)-N-Benzyloxycarbonyl-5-(4-benzyloxyphenyl)-4-methyl-5-hydroxyoxazolidine (2.1 g) prepared in Example 14 was processed as described in Example 9 to give the title compound (1.85 g) as pale yellow crystals in an yield of 95%.

Melting point: 88–90° C.; ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.43 (d, 3H, J=6.83 Hz), 5.13 (s, 2H), 5.15 (s, 2H), 5.28–5.31 (m, 1H), 5.88 (br, 1H), 7.03 (d, 2H, J=9.0 Hz), 7.31–7.44 (m, 10H), 7.96 (d, 2H, J=9.0 Hz); IR (KBr) ν_(max) 3374, 1712, 1690 cm⁻¹; Specific rotation: [α]^(D) ₂₄=−25° (C=1.00, CHCl₃); Optical purity: 98%ee (analysis conditions are as described in Example 3).

Example 16

Preparation of (4R)-N-benzyloxycarbonyl-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (Compound No.: 19030)

Preparation of a Grignard Reagent

To anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere were added magnesium metal (1.28 g) and iodine (20 mg). A solution of 2,4-difluorobromobenzene (9.65 g) in anhydrous tetrahydrofuran (30 mL) at room temperature was used as described in Example 12 to give a Grignard reagent.

Grignard Reaction

In anhydrous tetrahydrofuran (34 mL) was dissolved (4R)-N-benzyloxycarbonyl-4-methyl-5-oxazolidinone (10.6 g). The mixture was processed as described in Example 12 to give the title compound (10.7 g) as a diastereomer mixture as a pale yellow syrup in a yield of 68%.

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.52 and 1.51 (2d, 3H, J=6.8 Hz), 3.20–3.45 (m, 1H), 4.30–4.50 (m, 1H), 4.70–5.45 (m, 4H), 6.55–6.90 (m, 2H), 7.30–7.40 (m, 5H), 7.50–7.90 (m, 1H); IR (KBr) ν_(max) 3402, 1803, 1701, 1614 cm⁻¹.

Example 17

Preparation of (2R)-2-(benzyloxycarbonyl)amino-1-(2,4-difluorophenyl)-1-propanone (Compound No.: 25030)

In tetrahydrofuran (35 mL) was dissolved (4R)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (6.98 g) prepared in Example 16, and water (25 mL) and conc. hydrochloric acid (10 mL) were added. The mixture was processed as described in Example 13 to give the title compound (5.87 g) as pale yellow syrup in a yield of 92%.

¹H-NMR (CDCl₃, 400 MHz) δ ppm: 1.40 (d, 3H, J=7.0 Hz), 5.10 (s, 2H), 5.05–5.20 (m, 1H), 5.75–5.80 (m, 1H), 6.88–6.94 (m, 1H), 6.98–7.02 (m, 1H), 7.30–7.37 (m, 5H), 7.95–8.01 (m, 1H); IR (neat) ν_(max) 3358, 1718, 1681, 1611, 1532 cm⁻¹; Optical purity: 90%ee (analysis conditions are as described in Example 12).

INDUSTRIAL APPLICABILITY

According to the present invention, an optically active aminoalcohol derivative represented by general formula (5) or (6), which is useful as a production intermediate for a medicine or agricultural agent, can be produced stably in a large scale with an industrially adequate optical purity and a lower cost. This invention also provides an optically active 5-hydroxyoxazolidine derivative represented by general formula (3) as an important intermediate for production of the above optically active aminoalcohol derivative or other optically active amine derivatives and a generally usable preparation process therefor, as well as an optically aminoketone derivative represented by general formula (4) and a generally usable preparation process therefor. The production technique may be extensively applicable to preparation of optically active amine derivatives in addition to preparation of the above optically active aminoalcohol derivative, and thus is industrially excellent technique. 

1. A process for preparing an optically active aminoalcohol wherein an optically active 5-oxazolidinone derivative represented by general formula (1):

wherein R¹ represents an unprotected or optionally protected side chain in a natural α-amino acid; and R² represents optionally substituted aryl, optionally substituted alkyl, or optionally substituted aralkyl, is reacted with an organometallic reagent represented by general formula (2): R³—M  (2) wherein R³ represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen, to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹, R² and R³ are as defined above, which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4):

wherein R¹ and R³ are as defined above; and R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group, which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to stereoselectively provide an optically active aminoalcohol derivative represented by general formula (5):

wherein R¹, R³ and R⁴ are as defined above; provided that configuration of R¹ attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (5) is an erythro configuration.
 2. A process for preparing an aminoalcohol wherein an optically active 5-oxazolidinone derivative represented by a general formula (1):

wherein R¹ represents an unprotected or optionally protected side chain in a natural α-amino acid; and R² represents optionally substituted aryl, optionally substituted alkyl, or optionally substituted aralkyl, is reacted with an organometallic reagent represented by general formula (2): R³—M  (2) wherein R³ represents optionally substituted aryl or optionally substituted heterocycle; M represents one selected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen, to form an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹, R² and R³ are as defined above, which is then treated under acidic conditions to give an optically active aminoketone derivative represented by general formula (4):

wherein R¹ and R³ are as defined above; and R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group, which is then treated with a reducing agent or catalytically hydrogenated with a metal catalyst to provide an optically active aminoalcohol derivative represented by general formula (5):

wherein R¹, R³ and R⁴ are as defined above, and then, when R⁴ is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6):

wherein R¹ and R³ are as defined above; provided that configuration of R¹ attached to the asymmetric carbon at 4-position and the substituent represented by a nitrogen atom in the optically active 5-oxazolidinone represented by general formula (1) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol represented by general formula (6) is an erythro configuration.
 3. The process for preparing an optically active aminoalcohol as claimed in claim 1 or 2 wherein R¹ represents methyl, isopropyl, isobutyl, benzyl, hydroxymethyl, benzyloxymethyl, phenylthiomethyl, methylthiomethyl, alkyloxycarbonylmethyl or alkyloxycarbonylethyl; R² represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.
 4. The process for preparing an optically active aminoalcohol as claimed in claim 1 or 2 wherein R³ is represented by general formula (7):

wherein Y represents halogen; or by general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocycloalkyl.
 5. The process for preparing an optically active aminoalcohol derivative as claimed in claim 1 or 2 wherein R¹ represents methyl; and R³ is represented by general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.
 6. An optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; and wherein R² represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl.
 7. The optically active 5-hydroxyoxazolidine derivative as claimed in claim 6 wherein R³ is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.
 8. The optically active 5-hydroxyoxazolidine derivative as claimed in claim 7 wherein R¹ is methyl.
 9. A process for preparing an optically active 5-hydroxyoxazolidine derivative wherein an optically active 5-oxazolidinone derivative represented by general formula (1):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; wherein R² represents benzyl, tert-butyl, methyl, ethyl, isopropyl or 9-fluorenylmethyl, is reacted with an organometallic reagent represented by general formula (2): R³—M  (2) wherein R³ represents optionally substituted aryl or optionally substituted heterocycle; M is one selected from the group consisting of Li, MgX, ZnX, TiX₃ and CuX; and X represents halogen, to provide an optically active 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹, R² and R³ are as defined above.
 10. The process for preparing an optically active 5-hydroxyoxazolidine derivative as claimed in claim 9 wherein R³ is represented by general formula (7):

wherein Y represents halogen; or general formula (8):

wherein R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl.
 11. The process for preparing an optically active 5-hydroxyoxazolidine derivative as claimed in claim 10 wherein R¹ is methyl.
 12. The process for preparing an optically active 5-hydroxyoxazolidine derivative as claimed in claim 9 wherein M in general formula (2) is MgX wherein X is as defined above.
 13. An aminoketone derivative represented by

general formula (4a): wherein R^(1a) represents methyl; R^(4a) represents hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl; R^(3a) represents 4-benzyloxyphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl or 3-indolyl.
 14. A process for preparing an aminoketone derivative wherein a 5-hydroxyoxazolidine derivative represented by general formula (3):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R² represents optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl; and R³ represents optionally substituted aryl or optionally substituted heterocycle, is treated under acidic conditions to form an aminoketone derivative represented by general formula (4):

wherein R¹ and R³ are as defined above; R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group.
 15. An optically active alcohol derivative represented by general formula (5a):

wherein R^(1a) represents methyl; R^(3b) represents 4-benzyloxyphenyl; R^(4b) represents benzyloxycarbonyl; and configuration between the amino group and the hydroxy group is an erythro configuration.
 16. A process for preparing an optically active aminoalcohol derivative wherein an optically active aminoketone derivative represented by general formula (4b):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R^(3c) is represented by general formula (8):

wherein, R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, is catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol derivative

represented by general formula (5b): wherein R¹, R^(3c) and R⁴ are as defined above; provided that configuration of R¹ attached to the asymmetric carbon at 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (5b) is an erythro configuration.
 17. A process for preparing an optically active aminoalcohol derivative wherein an optically active aminoketone derivative represented by general formula (4b):

wherein R¹ represents an unprotected side chain or optionally protected side chain in a natural α-amino acid; R⁴ represents hydrogen or optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl or optionally substituted aralkyloxycarbonyl as a protective group; R^(3c) is represented by general formula (8):

wherein, R⁵ represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted phenyl, optionally substituted heterocycle or optionally substituted heterocyclealkyl, is catalytically hydrogenated with a metal catalyst, to stereoselectively form an optically active aminoalcohol represented by general formula (5b):

wherein R¹, R^(3c) and R⁴ are as defined above, and when R⁴ is a protective group, the amino group in the product is deprotected to give an optically active aminoalcohol derivative represented by general formula (6a):

wherein R¹ and R^(3c) are as defined above; provided that configuration of R¹ attached to the asymmetric carbon at 2-position and the substituent represented by a nitrogen atom in the optically active aminoketone derivative represented by general formula (4b) is not changed throughout these reactions and relative configuration between the amino group and the hydroxy group in the optically active aminoalcohol derivative represented by general formula (6a) is an erythro configuration. 